Emotional dysregulation, alexithymia and neuroticism: a systematic review on the genetic basis of a subset of psychological traits : Psychiatric Genetics

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Review article

Emotional dysregulation, alexithymia and neuroticism: a systematic review on the genetic basis of a subset of psychological traits

Castellini, Giovannia,*; Merola, Giuseppe Pierpaoloa,*; Baccaredda, Ottone Boya; Pecoraro, Vincenzoa; Bozza, Bernardoa; Cassioli, Emanuelea; Rossi, Eleonoraa; Bessi, Valentinab; Sorbi, Sandrob; Nacmias, Benedettab; Ricca, Valdoa

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Psychiatric Genetics ():10.1097/YPG.0000000000000335, December 20, 2022. | DOI: 10.1097/YPG.0000000000000335



It is now widely accepted that the psychological framework of each individual is shaped by a complex interplay of environmental, biological and genetic factors; the latter constitute an intriguing field of research, as a better understanding of the genomic variants concurring to a specific personality archetype or psychological trait may serve as an invaluable tool to comprehend and predict the intricacies of personal and collective mechanisms of information processing. Genetics has played a prominent role in psychiatric research since the very beginning of the era of etiological investigation of mental diseases (Burmeister et al., 2008), especially, regarding bipolar disorder and schizophrenia (Escamilla and Zavala, 2008; Henriksen et al., 2017). This intuition was later applied also to psychological and personality traits (Jang et al., 1996). Psychiatry genetics also benefitted greatly from recent advances in sequencing technologies; large-scale investigations such as genome-wide association studies (GWASs), in which thousands or even hundreds of thousands of genomes are correlated to a specific trait with a hypothesis-free approach, rather than considering a single gene-trait interconnection (Collins and Sullivan, 2013; Visscher et al., 2017), are now feasible.

Starting from this promising foothold, research into the field has expanded exponentially; among the various psychopathological domains, personality traits were one of the most obvious subjects to investigate, due to their unambiguous characterization (Rao and Broadbear, 2019), which retains its validity even in presence of potentially confounding sociocultural factors (Ayinde and Gureje, 2021) (at least, if compared to other psychological entities) (Zimmerman et al., 2015).

Most of the research on these topics employs the NEO Personality Inventory (named after its main original components, neuroticism, extraversion and openness to experiences) the same paper is already cited shortly after (McCrae), a well-recognized tool that explores five personality dimensions while providing an unparalleled perspective on multiple psychological domains (McCrae et al., 2005).

Some of these traits share numerous features and, rather than being distinct entities, contribute to complex personality structures that in certain occasions also predispose to psychiatric morbidity. One such case is constituted by alexithymia, emotional dysregulation and neuroticism, which all fall into a category characterized by inadequate, exaggerated or inhibited emotional responses, with frequent mood shifts and increased incidence of psychiatric conditions (Bradley et al., 2011; Ormel et al., 2013; Hemming et al., 2019). These entities in turn serve as a manifestation of this spectrum of features, hence identifying their common genetic roots might serve as an adequate instrument to describe the higher rank system encompassing them. These traits have an estimated heritability factor between 30 and 60% (evaluated through twin concordance studies) (Picardi et al., 2011; Hawn et al., 2015; Boomsma et al., 2018).

Several association analyses have been carried out on these traits (see the Materials and methods section); however, an investigation on their causative factors while considering them as a complex, multifacet – but still individual – entity might provide a whole new perspective on the subject. As shedding light on these constructs might prompt the development of new clinical and procedural approaches, and better understanding of their genetic basis might serve as a solid starting point, a review concerning these specific personality traits and their gene associations might as well prove valuable. To achieve this, the first step was to clearly define these traits separately, to subsequently merge the inferred information in a comprehensive report.


Neuroticism as a concept was first theorized explicitly by Eysenck around 1950 (Eysenck, 1952).

People high in neuroticism (both meant as test scores and theoretical conception) are more prone to negative emotions than average; they also tend to be more impulsive, less able to delay gratification and more likely to suffer from life stressors. Neuroticism can, thus, be defined as the tendency to experience negative emotions such as fear, anxiety, irritability, feelings of guilt and anger (Widiger and Oltmanns, 2007). These difficulties often heavily influence the individual’s ability to navigate effectively social contexts (Messina et al., 2010).

The concept of neuroticism is not only useful in the field of personality psychology but also when taking into account psychiatric clinical practice. In fact, it has been proven that people with high neuroticism scores have a higher chance of being diagnosed with a mental health disorder, especially regarding internalizing conditions such as anxiety and depressive disorders (Khan et al., 2005; Gale et al., 2016).

Currently, neuroticism is measured through a wide variety of scales. Perhaps the most well-known is the NEO Personality Inventory, a test made up of 240 items (McCrae et al., 2005). Other tests often used are Eysenck Personality Inventory (EPI) and Eysenck Personality Questionnaire (EPQ) (Knowles and Kreitman, 1965; Loo, 1979). Both these tests have a similar outlook on what ‘neuroticism’ means while differing in some aspects (Rocklin and Revelle, 1981).


The alexithymia construct, first introduced by Nemiah and Sifneos in the early 70s (Sifneos, 1986), was the point of arrival of a decades-long research into the cognitive style of patients with psychosomatic diseases. The salient features initially identified encompassed the difficulty in recognizing and describing feelings in the context of an externally oriented cognitive style, as well as the perplexity in distinguishing between feelings and the bodily sensations of emotional arousal. This inability to correctly interpret bodily inputs can often lead to psychosomatic symptoms and reduced insight. Moreover, alexithymia has been linked to psychopathology in the spheres of borderline personality disorder, eating disorders and psychosis (Mannarini et al., 2016). Neuroscientific studies on alexithymia point toward the importance of amygdala functioning (Goerlich, 2018).

The main tools for the evaluation of alexithymia are the Toronto Alexithymia Scale (Taylor et al., 2003) and the Schalling-Sifneos Personality Scale (Sifneos, 1986). Alexithymia has been often associated with several psychopathological conditions, most prominently depression and eating disorders (Taylor, 1984). Upon the realization of its validity in the clinical and research fields, alexithymia was included as an item in various assessment and diagnostic questionnaires and furtherly investigated by dedicated inventories (Sifneos, 1973; Montagne et al., 2007; de Vroege et al., 2018).

Emotion dysregulation

Emotion dysregulation (ED) is a wide and multifacet psychological concept (Thompson, 2019). It encompasses several different psychological traits and is associated with Borderline personality disorder (Carpenter and Trull, 2013), autism spectrum disorders (Cai et al., 2018), attention deficit hyperactivity disorder (Shaw et al., 2014), post traumatic disorder (Powers et al., 2015) and bipolar disorder (Bayes et al., 2016). Moreover, it often leads to substance abuse (Garke et al., 2021), self-harm (Gratz and Roemer, 2008) or even suicidal behavior (Raudales et al., 2020). ED is thought to be connected to abuse and trauma, especially during childhood (Dvir et al., 2014). This personality feature is characterized by incapacity or difficulty in modulating emotions in order to fit them to the social context. People with ED often suffer from poorer attention, labile mood and overly intense emotions. This trait often produces abnormal behavior both in the externalizing and internalizing spectrum. ED has been shown to be linked to neuroticism (Paulus et al., 2016), and interestingly, there is even evidence of this connection from a neuroscientific standpoint (Yang et al., 2020; Silverman et al., 2019). According to Gratz and Roemer (2004), ED can be defined as a deficit in awareness and acceptance of emotions, with a lack of control of one’s impulsive behavior. As such, ED often results in difficulties in employing appropriate strategies in social contexts.

Due to its broad definition, ED is investigated through a variety of scales, such as Difficulties in Emotion Regulation Scale (Gratz and Roemer, 2004), Emotion Dysregulation Scale (Powers et al., 2015), Emotional Expressivity Scale (Burgin et al., 2012), Connor-Davidson Resilience Scale (Connor and Davidson, 2003), Emotion Regulation Checklist (Shields and Cicchetti, 1997), Personality Assessment Inventory (Venta et al., 2018) and Sleep and Emotional Reactivity in Alcohol Use Disorder (NCT04979507, 2021). The multitude of instruments employed to assess ED might strengthen the belief that it might be a somewhat ill-defined concept in current literature (Cole, 2014); this translates into the tendency to study it from different perspectives and angles. However, such a tendency might as well negatively affect the reproducibility of the samples, which were attributed this trait by using different scales.


The aim of this systematic review is to investigate the influence of genetics on these three traits and to categorize known data on the subject, both from a GWAS and genetic association study perspective.

Materials and methods

This review adheres to the 2020 PRISMA guidelines (Page et al., 2021).

Eligibility criteria

Included articles were observational studies, either cross-sectional or longitudinal. The inclusion criteria were as follows: original article, written in English, reporting results of genetic analysis on humans in combination with measurements of neuroticism, ED or alexithymia using validated tools (questionnaires or tasks). The main outcome measures were all associations of either neuroticism, ED or alexithymia with specific alleles or intergenic variants. Exclusion criteria were: the study being a systematic review, a meta-analysis, an opinion article and methodological or technical contributions with no analysis over clinical data.

Information sources and search strategy

The authors used the electronic database PubMed in order to select studies. The following string was used for the systematic search:

(emotion regulation[Title/Abstract] OR emotion dysregulation[Title/Abstract] OR alexithymia[Title/Abstract] OR neuroticism[Title/Abstract]) AND (genetics OR gene OR genome OR GWAS OR genome-wide association study) NOT review[pt] NOT systematic review[pt] NOT meta-analysis[pt] AND eng[la].

The last search was run on 14 July 2021.

Selection process

Three authors (O.B.B, G.P.M. and V.P.) independently assessed the abstracts of potentially eligible studies. Eligibility assessment was performed in an unblinded standardized manner. If there was doubt about whether the study was eligible for inclusion, the reviewers examined the full text of the articles. The published protocol required consensus in case the authors disagreed on the inclusion of a specific study. In case, the opinion was not unanimous, a majority vote would have been taken between all authors. The authors agreed on all the eligibility assessments of the studies, and no consensus vote needed to take place.

Data collection process and data items

Four authors (O.B.B., V.P., G.P.M. and B.B.) independently extracted the following categories of data from each included study: study design (GWAS or genetic association), population (number of subjects, ethnicity), genes studied, polymorphisms and their effect on the traits.

Risk of bias

Risk of bias for individual studies was assessed using the STrengtheningthe REportingof Genetic Association Studies variant of the STROBE checklist for genetic association studies (Little et al., 2009). GWAS were not assessed through risk of bias, as no proper tool is available for such aim. An online tool was used to produce the summary graph S1 (McGuinness and Higgins, 2021).


A total of 1340 studies were found after running the search line through PubMed. Three hundred one studies were included for evaluation of the manuscript, 1039 were excluded on the basis of title and abstract and 99 were excluded after manuscript review and application of inclusion criteria. Two hundred two studies (Rinieris et al., 1980; Ball et al., 1997; Gelernter et al., 1998; Jorm et al., 1998, 2000; Deary et al., 1999; Flory et al., 1999; Gustavsson et al., 1999; Sirota et al., 1999; Du et al., 2000; Greenberg et al., 2000; Henderson et al., 2000; Lerman et al., 2000; Persson et al., 2000; Sher et al., 2000; Jang et al., 2001; Close Kirkwood et al., 2002; Stoltenberg et al., 2002; Brummett et al., 2003; Eley et al., 2003; Fullerton et al., 2003; Sen et al., 2003,2004; Umekage et al., 2003; Westberg et al., 2003,2009; Jacob et al., 2004; Samochowiec et al., 2004; Tsai et al., 2004; Ham et al., 2005; Kato et al., 2005; Kusumi et al., 2005; Lang et al., 2005; Neale et al., 2005; Olsson et al., 2005; Tochigi et al., 2005, 2006; Wacker et al., 2005; Willis-Owen et al., 2005; Beem et al., 2006; Dragan and Oniszczenko, 2006; Hettema et al., 2006,2008, 2009, 2013,2015; Hibino et al., 2006; Hoth et al., 2006; Koller et al., 2006; van Rijn et al., 2006; Fiocco et al., 2007,2009; Gatt et al., 2007; Gutknecht et al., 2007; Hünnerkopf et al., 2007; Middeldorp et al., 2007, 2010, 2010; Pascual et al., 2007; Urata et al., 2007; Waga and Iwahashi, 2007; Wasserman et al., 2007; Wray et al., 2007, 2008, 2008, 2009; Gillespie et al., 2008; Heck et al., 2008; Kazantseva et al., 2008,2011; Rietschel et al., 2008; Shifman et al., 2008; van den Oord et al., 2008; Wachleski et al., 2008; Harro et al., 2009; Joffe et al., 2009; Juhasz et al., 2009,2010; Kochanska et al., 2009; Murakami et al., 2009; Schmitz et al., 2009; Terracciano et al., 2009,2010; Unschuld et al., 2009; Antypa and Van der Does, 2010; Calboli et al., 2010; Luciano et al., 2010,2012,2018,2021; Vinberg et al., 2010; Zuo et al., 2010; DeYoung et al., 2011; Ellis et al., 2011; Swart et al., 2011; Verschoor and Markus, 2011; Walter et al., 2011; Amin et al., 2012; Amstadter et al., 2012; Boscarino et al., 2012; Dar-Nimrod et al., 2012; Jutras-Aswad et al., 2012; Kano et al., 2012; Kuepper et al., 2012; Kurrikoff et al., 2012; Markus and Capello, 2012; McIntosh et al., 2012; Montag et al., 2012,2013; Pełka-Wysiecka et al., 2012; Propper et al., 2012; Wahlstrom et al., 2012; Wingbermühle et al., 2012; Aragam et al., 2013; Barbato et al., 2013; Glocke et al., 2013; Grazioplene et al., 2013; Kim et al., 2013,2015; Kuhnen et al., 2013; Lehto et al., 2013,2015,2016; Mandelli et al., 2013; Markus, 2013; Strohmaier et al., 2013; Zayats et al., 2013; Chang et al., 2014,2017,2020; Criado et al., 2014; Gong et al., 2014; Haram et al., 2014; Laas et al., 2014; Lovallo et al., 2014; Plieger et al., 2014; Weiss et al., 2014; Jurczak et al., 2015; Koh et al., 2015,2016; Kotyuk et al., 2015; Kruschwitz et al., 2015; Mezzavilla et al., 2015; Narita et al., 2015,2018; Peciña et al., 2015; Roelofs et al., 2015; Voigt et al., 2015; Jung et al., 2016; Larsen et al., 2016; Madsen et al., 2016; Okbay et al., 2016; Petito et al., 2016; Powers et al., 2016; Schneider-Hassloff et al., 2016; Schneider-Matyka et al., 2016; Smith et al., 2016; Fan et al., 2017; Halldorsdottir et al., 2017; Iliadis et al., 2017; Lo et al., 2017; Viddal et al., 2017; Xu et al., 2017; Bîlc et al., 2018; Bizaoui et al., 2018; Chapman et al., 2018; Nagel et al., 2018,2020; Noroña et al., 2018; Panitz et al., 2018; Sacchinelli et al., 2018; Terock et al., 2018, 2021; Turley et al., 2018; Yen et al., 2018; An et al., 2019; Chong et al., 2019; Luo et al., 2019; Michałowska-Sawczyn et al., 2019; Rodríguez-Ramos et al., 2019; Zou et al., 2019; Grzywacz et al., 2020; Hill et al., 2020; Hou et al., 2020; Kataja et al., 2020; Li et al., 2020; Morris et al., 2020; Salinas et al., 2020; Suchanecka et al., 2020; Tabak et al., 2020; Vaht et al., 2020; Zhao and Liu, 2020; Belonogova et al., 2021; Byrd et al., 2021; Heilbronner et al., 2021; Nestor et al., 2021) were finally selected: 27 GWAS and 175 observational genetic association studies. Of the latter, 142 were on neuroticism, 20 on alexitimia and 13 on emotional dysregulation (Fig. 1). Full results are shown in Supplementary Material S2, Supplemental Digital Content 1, https://links.lww.com/PG/A295, due to the unwieldy size of the result table. Below are the results concerning the most represented genes among the genetic association studies on neuroticism: serotonin transporter (SLC6A4, Table 1), catechol-ortho-methyltransferase (COMT, Table 2), monoamine oxidase type A (MAO-A, Table 3) and brain-derived neurotrophic factor (BDNF, Table 4). The outcomes of the screening on alexithymia are shown in Table 5 and on ED in Table 6. Results concerning GWAS studies are shown in Table 7.

Table 1 - SLC6A4 review results (neuroticism)
Authors Publication year Tool used to assess neuroticism Polymorphisms studied Genetic association (S = short allele; L = long allele) Sample population
Antypa and Van der Does 2010 NEO-PI-R 5-HTTLPR biallelic and triallelic - 250 Dutch students (mostly females)
Ball et al. 1997 NEO-FFI 5-HTTLPR biallelic, STIN2-VNTR - 2085 German twins
Brummett et al. 2003 NEO-PI-R 5-HTTLPR biallelic L 103 depressed patients and 99 controls
Chang et al. 2017 MPI 5-HTTLPR triallelic (rs25531G coded equivalent to S) S, both biallelic and triallelic (only in men) 1340 Taiwaneses
Chang et al. 2020 MPI 5-HTTLPR triallelic S in males, L in females 2236 Han Chinese adults, including 736 patients with GAD and 1500 healthy participants
Deary et al. 1999 NEO-FFI 5-HTTLPR biallelic, STIN2-VNTR - 809 men and 783 women from Scotland
Dragan and Oniszczenko 2006 NEO-FFI 5-HTTLPR biallelic S 200 Polish (only females)
Du et al. 2000 NEO-FFI 5-HTTLPR biallelic S (only in males) 186 Canadians
Flory et al. 1999 NEO-FFI 5-HTTLPR biallelic - 271 Americans
Gelernter et al. 1998 NEO-FFI 5-HTTLPR biallelic, STIN2-VNTR - 322 Americans
Greenberg et al. 2000 NEO-PI-R 5-HTTLPR biallelic S 397 American sisters (thus females only)
Gustavsson et al. 1999 KSP 5-HTTLPR biallelic, STIN2-VNTR - Two healthy samples from Sweden (127 and 178)
Harro et al. 2009 EBBFI 5-HTTLPR biallelic S 1176 Estonian children
Hettema et al. 2015 NEO-FFI, EPQ 5-HTTLPR biallelic, rs3813034, rs140701, rs6354, rs2020936 - 928 Americans
Jacob et al. 2004 NEO-PI, TPQ 5-HTTLPR biallelic S (only within Cluster C patients) 320 patients with personality disorders (mainly cluster B and C) and 281 healthy controls, from Germany
Jang et al. 2001 NEO-PI-R 5-HTTLPR biallelic S 388 American siblings
Jorm et al. 1998 EPQ-R 5-HTTLPR biallelic - 759 Polish
Juhasz et al. 2010 NEO-PI-R, BFI 5-HTTLPR biallelic - 1188 English (history of anxious or depressive psychopathology)
Jurczak et al. 2015 NEO-FFI 5-HTTLPR biallelic - 272 healthy women from northern Poland in postmenopause
Kazantseva et al. 2008 EPI 5-HTTLPR biallelic, STIN2-VNTR STIN2 301 healthy Russians
Kruschwitz et al. 2015 NEO-FFI 5-HTTLPR triallelic S 178 Germans
Kuepper et al. 2012 FPI-R 5-HTTLPR triallelic - 357 University students from Germany
Kuhnen et al. 2013 NEO-SF 5-HTTLPR biallelic S 60 Americans
Lerman et al. 2000 EPI 5-HTTLPR biallelic - 185 American smokers
Lovallo et al. 2014 EPQ 5-HTTLPR triallelic (rs25531G coded equivalent to S) S (only in subjects with history of alchohol abuse disorder) 314 Americans
Luo et al. 2019 BFI 5-HTTLPR triallelic (rs25531G coded equivalent to S) - 397 Americans
Madsen et al. 2016 NEO-PI-R 5-HTTLPR triallelic - 76 healthy individuals from Denmark
Markus 2013 Dutch personality inventory 5-HTTLPR triallelic (rs25531G coded equivalent to S) - 771 Dutch (mostly females)
Markus and Capello 2012 DPQ 5-HTTLPR triallelic - 857 Dutch students
Middeldorp et al. 2007 ABV 5-HTTLPR biallelic - 559 parents and 1245 twins, Dutch
Middeldorp et al. 2010 ABV 5-HTTLPR biallelic - 126 fathers, 135 mothers, 87 monozygotic male twins, 161 monozygotic female twins, 238 DZ male twins/brothers and 408 DZ female twins/sisters from 438 families (Dutch)
Nestor et al. 2021 NEO-PI-R 5-HTTLPR biallelic - 100 healthy participants from the USA
Pascual et al. 2007 ZKPQ 5-HTTLPR biallelic, STIN2-VNTR - 65 borderline-disorder patients
Pelka-Wysiecka et al. 2012 NEO-FFI 5-HTTLPR biallelic - 406 healthy Polish
Petito et al. 2016 NEO-FFI 5-HTTLPR biallelic S 131 elite Italian athletes (only males)
Plieger et al. 2014 NEO-FFI 5-HTTLPR biallelic and triallelic - 1075 Germans (mostly females)
Salinas et al. 2020 NEO-FFI 5-HTTLPR biallelic S 76 patients from Chile with Borderline Personality Disorder (mostly females)
Samochowiec et al. 2004 NEO-FFI 5-HTTLPR biallelic - 100 Polish
Schneider-Matyka et al. 2016 NEO-FFI 5-HTTLPR biallelic - 214 women in postmenopause from northern Poland
Sen et al. 2004 NEO-PI 5-HTTLPR biallelic S 384 Americans (mostly females)
Sher et al. 2000 NEO-PI-R 5-HTTLPR biallelic S 236 Americans (mostly females)
Sirota et al. 1999 NEO-PI-R 5-HTTLPR biallelic - 902 Americans
Stoltenberg et al. 2002 NEO-FFI 5-HTTLPR biallelic - 161 individuals from families with history of alcoholism (USA)
Terracciano et al. 2009 NEO-PI-R 5-HTTLPR triallelic, rs1906451, rs435622, rs8076005, rs11080122, rs2020939, rs2020936, rs1487971, rs25603446 - 1182 Italians (Sardinia)
Umekage et al. 2003 NEO-PI-R 5-HTTLPR biallelic - 244 Japanese (mostly females)
Verschoor et al. 2011 DPQ 5-HTTLPR triallelic - 94 Dutch students selected from a larger sample for extreme values of neuroticism on both ends
Vinberg et al. 2010 EPQ 5-HTTLPR biallelic S 204 high-risk and 204 low-risk twins (Danes)
Wachleski et al. 2008 MMPI 5-HTTLPR biallelic - 67 patients with panic disorder from Brazil
Willis-Owen et al. 2005 EPQ 5-HTTLPR biallelic - 1001 English (selected for extreme values of neuroticism on both ends)
Wray et al. 2009 EPQ, TPQ rs2020934, rs6355, rs6354, rs2020936, 5-HTTLPR biallelic, rs28914832, rs140700, rs6355, rs6354, rs2020939, rs2020935, rs4251417, rs2020930, rs7214991, rs1050565, rs4251417 - 1161 depressed/anxious, 1051 controls, Australian twins

Table 2 - Catechol-ortho-methyltransferase review results (neuroticism)
Authors Publication year Tool used to assess neuroticism Polymorphisms studied Genetic association Sample population
Boscarino et al. 2012 NEO-FFI rs4680 Not reported (sum of risk allele: -) 412 American chronic pain patients
Eley et al. 2003 NEO-FFI rs4680 - 2085 German twins
Henderson et al. 2000 EPQ rs4680 - 862 Australians and 1465 as replication sample
Hettema et al. 2015 NEO-FFI, EPQ-R rs4680, rs165599 rs4680, rs4680-rs165599 (unreported allele, AA, females only) 928 Americans
Hoth et al. 2006 NEO-FFI rs4680 - 486 healthy Americans
Kotyuk et al. 2015 NEO-FFI rs4680 AA 616 elderly from the USA
Lehto et al. 2013 NEO-FFI rs4680 GG (in 25 years old females; heterozygous were protected) 593 participants from Estonia split in three different age group: 15, 18, and 25 years
Luciano et al. 2010 NEO-FFI rs4680 - 1641 elderly from Scotland
Olsson et al. 2005 NEO-FFI rs4680 - 962 adolescents from Australia
Panitz et al. 2018 NEO-FFI rs4680 - 383 Germans
Pelka-Wysiecka et al. NEO-FFI rs4680 GG (in males) 406 healthy Polish
Tochigi et al. 2006 NEO-PI-R rs4680 Sum of risk allele 256 Japanese, employed in an hospital (mostly females)
Urata et al. 2007 NEO-FFI rs4680 - 219 Japanese students (mostly females)
Wray et al. 2008 EPQ-R rs4680 - 2045 Australians from 987 families

Table 3 - Monoamine oxidase type A review results (neuroticism)
Authors Publication year Tool used to assess neuroticism Polymorphisms studied Genetic association Sample population
Eley et al. 2003 NEO-FFI MAO-A VNTR >3.5 repetitions (in males) 2085 German twins
Jorm et al. 2000 EPQ-R MAO-A VNTR - 2725 Australians
Jurczak et al. 2015 NEO-FFI MAO-A VNTR - 272 healthy women from northern Poland in postmenopause
Pelka-Wysiecka et al. 2012 NEO-FFI MAO-A VNTR - 406 healthy Polish
Rodríguez-Ramos et al. 2019 BFI MAO-A VNTR >3 repetitions (only in females) 99 women from Spain
Samochowiec et al. 2004 NEO-FFI MAO-A VNTR - 100 Polish
Schneider-Matyka et al. 2016 NEO-FFI MAO-A VNTR - 214 women in post-menopause from northern Poland
Tochigi et al. 2006 NEO-PI-R MAO-A VNTR sum of risk alleles 256 Japanese, employed in an hospital (mostly females)
Urata et al. 2007 NEO-FFI MAO-A VNTR, rs6323 - 219 Japanese students (mostly females)
Xu et al. 2017 MPI rs3788862, rs5906957, rs979606 - 1160 men and 1180 women from the Netherlands

Table 4 - Brain-derived neurotrophic factor review results (neuroticism)
Authors Publication year Tool used to assess neuroticism Polymorphisms studied Genetic association Sample population
Gatt et al. 2007 NEO-FFI rs6265 AA 169 controls and 39 subclinical depressed patients from Australia
Hünnerkopf et al. 2007 NEO-PI-R rs6265 - 272 healthy volunteers from Germany
Joffe et al. 2009 NEO-FFI rs6265 - 467 nonclinical Caucasian subjects
Jung et al. 2016 NEO-FFI rs6265 AA in controls, GG in subjects who practiced meditation 64 controls and 72 subjects practicing meditation from Korea
Lang et al. 2005 NEO-FFI rs6265 - 343 Germans
Lehto et al. 2016 EBBFI rs6265 - 593 (age 15), 417 (age 18), 487 (age 25), all Estonian
Luciano et al. 2010 NEO-FFI rs6265 - 1641 elderly from Scotland
Nestor et al. 2021 NEO-PI-R rs6265 AA 100 healthy participants from the USA
Salinas et al. 2020 NEO-FFI rs6265 - 76 patients from Chile with Borderline Personality Disorder (mostly females)
Sen et al. 2003 NEO-FFI rs6265 GG 441 Americans
Tsai et al. 2004 TPQ rs6265 - 114 healthy Chinese female volunteers
Willis-Owen et al. 2005 EPQ rs6265 - 571 English people and 4843 Americans
Wray et al. 2008 EPQ-R rs6265 - 2045 Australian twins sampled for extreme values of neuroticism on both ends from a larger sample

Table 5 - Alexithymia review results
Authors Publication year Tool used to assess alexithymia Genes Polymorphisms studied Genetic association Sample population
Gong et al. 2014 TAS 5-HTR1A rs6295 G 504 Chinese Han students
Ham et al. 2005 TAS SLC6A4, COMT rs4680, 5-HTTLPR biallelic COMT: GG 109 students from Korea
Kano et al. 2012 TAS SLC6A4 5-HTTLPR biallelic L 304 healthy Japanese participants
Koh et al. 2016 TAS COMT rs4680 GG (both on total score and in subscores) 244 patients with OCD from Korea
Koh et al. 2015 TAS OXTR rs237885, rs237887, rs2268490, rs4686301, rs2254298, rs13316193, rs53576, and rs2268498 - 355 patients with obsessive-compulsive disorder (234 men, 121 women) from Korea
Li et al. 2020 TAS 5-HTR2A rs6311 rs6311 602 Han Chinese
Mandelli and Serretti 2013 SPSS SLC6A4 rs25531 - 64 Italians with alchohol and other substances abuse history
Roelofs et al. 2015 BVAQ Rasopathies, Turner Noonan Syndrome and Turner Syndrome (X0) X0 Females only sample, Dutch. 40 individuals with Turner Syndrome, 40 with Noonan Syndrome and 40 controls.
Sacchinelli et al. 2018 TAS SLC6A4 5-HTTLPR biallelic - 115 healthy Italians
Schneider-Hassloff et al. 2016 CAS OXTR rs53576 - 195 Germans
Swart et al. 2011 BVAQ COMT rs4680 AA (only in verbalizing subscale) 493 undergraduate university students from Netherlands
Terock et al. 2018 TAS SLC6A4 5-HTTLPR triallelic (rs25531G coded equivalent to S) L 5283 Germans
Terock et al. 2021 TAS VDBP rs4588, rs7041 - 5783 Germans
Terock et al. 2021 TAS 5-HTR1A, 5-HTR2A 5HTR1A: rs6295 5-HTR2A: rs6311 - 3708 Germans
van Rijn et al 2006 BVAQ Klinefelter XXY XXY 32 Klinefelter and 26 male controls (Dutch)
Voigt et al. 2015 TAS BDNF, DRD2/ANKK1 rs1800497, rs6265 - 143 healthy individuals
Wahlstrom et al. 2012 TAS DRD2/ANKK1 rs1800497 - 120 Undergraduate classified as ‘binge drinkers’ from the USA
Walter et al. 2011 TAS BDNF, DRD2/ANKK1 rs6265, rs1800497 - (association present only in combination) 664 Germans
Wingbermühle et al. 2012 TAS, BVAQ Rasopathies Noonan Syndrome and Turner Syndrome (X0) Noonan Syndrome 40 Dutch with Noonan Syndrome (various genes) and 40 controls
Zou et al. 2019 TAS BDNF rs6265 AA (both cases and controls) 223 Han Chinese people with panic disorder and 218 controls

Table 6 - Emotion dysregulation review results
Authors Publication year Tool used to assess emotion dysregulation Genes Polymorphisms studied Genetic association Sample population
Amstadter et al. 2012 BIRD SLC6A4, COMT 5-HTTLPR biallelic, rs4680 5-HTTLPR biallelic, rs4680 (distress tolerance) 218 early adolescents
Bîlc et al. 2018 Tasks BDNF rs6265 - 266 students from Romania
Byrd et al. 2020 PAI-BOR OXTR rs53576, rs2254298 rs53576 (GG) 2450 American female children (5-8 years)
Halldorsdottir et al. 2017 CERQ FKBP5 rs9296158, rs3800373, rs1360780, rs9470080 - 1345 genotyped adolescents of Portuguese descent
Jorm et al. 2000 STSC SLC6A4 5-HTTLPR biallelic - 660 Australian children (3-15 years)
Kataja et al. 2020 Tasks TPH2 rs4570625 - 330 Finnish children (8 months of age)
Kochanska et al. 2009 Tasks SLC6A4 5-HTTLPR biallelic - (association present only in ‘insecurely attachment’ sample) 89 American children
Murakami et al. 2009 Tasks SLC6A4 5-HTTLPR biallelic S 24 undegraduate and graduate students from Japan
Noroña et al. 2018 DCS SLC6A4 5-HTTLPR triallelic (rs25531G coded equivalent to S) - 99 children aged 3 from the USA
Propper et al. 2012 ERC (assessed by teachers) DRD2, DRD4 DRD4: VNTR EX3, DRD2: rs1800497 rs1800497 (in males) 206 children, evaluated through ERC by teachers and parents.
Viddal et al. 2017 ERC SLC6A4 5-HTTLPR biallelic S (association present only at age 6) 602 Norwegian children
Weiss et al. 2014 SEAS SLC6A4, COMT 5-HTTLPR biallelic COMT: rs4680 COMT: G (in the Intra-personal Domain) 289 healthy women from Germany
Yen et al. 2018 ASQ ER ESR α-Xbal G 100 Taiwanese women with PMMD; 96 controls

Table 7 - Genome-wide association studies review results
References Author (s) Publication year Tool used to assess neuroticism Highly significant results a Summary of overall results concerning trait of interestb Sample population Trait
The Heidelberg Five’ personality dimensions: Genome-wide associations, polygenic risk for neuroticism, and psychopathology 20 years after assessment Heilbronner et al. 2021 A combination of questionnaires including EPI, STAI-S and others defining a condition interpreted as ‘Emotional Lability’ (ELAB) - rs112852264, rs34464186, rs12746528, rs66583506, rs12750662 (unknown category) intergenic: rs2344174, rs34351096, rs17131127, rs35147867 intron: rs7001432 (CSMD1) HeiDE study (‘Heidelberger Langzeitstudie zu Risikofaktoren und Diagnose chronischer Erkrankungen’); 5133 Germans EMOTIONAL DYSREGULATION
A genome scan of neuroticism in nicotine dependent smokers Neale et al. 2005 EPQ - - 129 families (843 siblings) from the USA NEUROTICISM
A genome-wide association study of emotion dysregulation: Evidence for interleukin 2 receptor alpha Powers et al. 2016 EDS Intron: rs6602398 (ILR2A, only in males) Intron: rs6602398 (ILR2A, only in males) 2600 African American from the USA EMOTIONAL DYSREGULATION
A genome-wide association study of neuroticism in a population-based sample Calboli et al. 2010 EPQ - 6 genes: MGC57346, MSRA, XKR6, C17ORF69, KIAA1267 (integrative analysis of genomic and transcriptomic data of genome-wide association study (GWAS) and expression quantitative trait locus (eQTL) study) UK Biobank, Psychiatric Genomics Consortium NEUROTICISM
A genome-wide linkage study of individuals with high scores on NEO personality traits Amin et al. 2012 NEO-FFi - - 2657 Dutch NEUROTICISM
A genome-wide scan for Eysenckian personality dimensions in adolescent twin sibships: psychoticism, extraversion, neuroticism, and lie Gillespie et al. 2008 EPI - Regions on chromosome 16 and 19 1280 Australian adolescent twins and their siblings NEUROTICISM
A whole genome association study of neuroticism using DNA pooling Shifman et al. 2008 EPQ-R - - 2000 English people and 1500 English people for replication sample: all of them oversampled for high neuroticism scores NEUROTICISM
Analysis of functional variants reveals new candidate genes associated with alexithymia Mezzavilla et al. 2015 TAS Exons: rs144957058 (TMEM88B), rs45575636(ABCB4), rs35942033 (TP53AIP1), rs35287114 (ARHGAP32) 585 healthy adults from the Friuli Venezia Giulia Genetic Park project ALEXITHYMIA
Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism Luciano et al. 2018 EPQ-R-S Intergenic: rs72694263, rs7107356, rs7111031, rs2953805, rs10097870, rs2921036 intronic: rs169235 (CACNA1E), rs1521732 (LINGO2, LOC105376004), rs1422192 (LINC00461), rs7175083 (LINGO1), rs7502590 (BAIAP2), rs11082011 (CELF4), rs6982308 (MSRA), rs7005884 (XKR6) UTR3: rs11090045 (ZC3H7B) UTR3: rs11090045 (ZC3H7B) 116 loci UK Biobank NEUROTICISM
Gene-based association analysis identifies 190 genes affecting neuroticism Belonogova et al. 2021 EPQ-RS 57 noncoding variants; Exons: TRIM39-RPP21, RPP21, C12orf49 190 genes UK Biobank NEUROTICISM
Genetic contributions to two special factors of neuroticism are associated with affluence, higher intelligence, better health, and longer life Hill et al. 2020 EPI 10 intron SNPs, 7 intergenic SNPs, 1 UTR3 (PAX6), 1 exon (DCAF5), 1 upstream (FBXL17) 51 loci UK Biobank NEUROTICISM
Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses Okbay et al. 2016 EPI Intron: rs10960103 (AKAP8P1,JKAMPP1), rs4938021 (LOC105369501), rs139237746 (SBF2), rs1557341 (CELF4), rs12938775 (PAFAH1B1), rs12961969 noncoding transcript variant: rs35688236 (LOC102724048), rs2150462, rs12903563, rs2572431 (inversion-tagging polymorphism on chromosome 8), rs193236081b (Inversion-tagging polymorphism on chromosome 17) 11 loci UK Biobank, Psychiatric Genomics Consortium, Resource for Genetic Epidemiology Research on Aging NEUROTICISM
Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci Smith et al. 2016 Intergenic: rs490647, rs12637928, rs12378446, rs4977844 intron: rs4653663 (VRK2), rs62353264 (TMEM192), rs12682352 (MFHAS1), rs111433752 (LINC02210-CRHR1), rs1187264 (RPL12P40) 9 loci UK Biobank, Scottish Family Health Study (6659), Queensland Institute of Medical Research Berghofer Medical Research Institute cohort (8687) NEUROTICISM
Genome-wide association analysis followed by a replication study implicates a novel candidate gene for neuroticism van den Oord et al. 2008 EPQ-R - - 1227 people from the USA NEUROTICISM
Genome-wide association scan for five major dimensions of personality Terracciano et al. 2010 NEO-PI-R - rs3026815, rs6047641, rs1159275, rs7329003 6148 people from an isolated community in Sardinia, 3900 in the replication sample NEUROTICISM
Genome-wide association study of the five-factor model of personality in young Korean women Kim et al. 2013 NEO-PI-R - GWAS: OR1A2 1089 Korean women NEUROTICISM
Genome-wide association study of the sensitivity to environmental stress and adversity neuroticism cluster Nagel et al. 2020 EPQ - 47 loci UK Biobank NEUROTICISM
Genome-wide association uncovers shared genetic effects among personality traits and mood states Luciano et al. 2012 EPQ - Genes: LCE3C, SCAMP2, POLR3A, ULK3, LMAN1L Croatia (800), Scotland (400), England (1500), Netherlands (1300) NEUROTICISM
Integrating genome-wide association study and expression quantitative trait loci data identifies multiple genes and gene set associated with neuroticism Fan et al. 2017 EPI - UK Biobank, Psychiatric Genomics Consortium NEUROTICISM
Integrative analysis of genome-wide association study and common meQTLs for exploring the effects of DNA methylation on the development of neuroticism Zhao and Liu 2020 EPI - 11 genes identified through integrative analysis UK Biobank, Psychiatric Genomics Consortium NEUROTICISM
Item-level analyses reveal genetic heterogeneity in neuroticism Nagel et al. 2018 EPQ-R-SF 117 loci (not reported any information on subdivision between introns, intergenic or exons) 117 loci associated with overall neuroticism score, 138 item-specific UK Biobank NEUROTICISM
Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism Fullerton et al. 2003 EPQ - Five regions: 1q, 4q, 7p, 12q and 13q 34580 sibling pairs in the southwest of England NEUROTICISM
Modeling prior information of common genetic variants improves gene discovery for neuroticism Lo et al. 2017 BFI Intergenic: rs12102100 intron: rs9822731 (CADM2), rs17022974 (CADM2), rs10812851 (LINGO2, LOC105376004), rs9611505 (EP300) Combination of relative enrichment score (RES) and conditional false discovery rate (FDR): CADM2, LINGO2 and EP300 23 and Me database, UK Biobank, Psychiatric Genomics Consortium NEUROTICISM
Multitrait analysis of genome-wide association summary statistics using MTAG Turley et al. 2018 EPI Noncoding transcript variant rs2572431(LINC00529), rs1187229 (LOC105372072, LOC105372073) intron: rs62057143 (CRHR1, LINC02210-CRHR1), rs10960103 (AKAP8P1,JKAMPP1), rs60827133, rs4938021 (LOC105369501), rs1557341 (CELF4), rs8084351 (DCC), rs10733389, rs10113343 (PINX1), rs9893575 (LOC105371490), rs716804 (SBF2) 37 loci UK Biobank NEUROTICISM
Pathway analysis of genome-wide association datasets of personality traits Kim et al. 2015 NEO-PI-R L1CAM pathway and associated genes Pathway analysis: L1CAM pathway and associated genes 1089 Korean women NEUROTICISM
The influence of X chromosome variants on trait neuroticism Luciano et al. 2021 EPQ-R-SF intergenic: rs6630665, rs764018176, rs177010 intronic: rs5977754 (HS6ST2) 204 loci on chromosome X UK Biobank NEUROTICISM
TMPRSS9 and GRIN2B are associated with neuroticism: a genome-wide association study in a European sample Aragam et al. 2013 NEO-FFI - GWAS: TMPRSS9 NESDA cohort 2008 (2000 Dutch) NEUROTICISM
aP equal or lower than 10−8.
bIf not otherwise specified, P value threshold: 5 × 10−6.

Fig. 1:
Flow diagram.

For each category, the following number of studies was found: SLC6A4 (50), COMT (13), MAO-A (9) and BDNF (12). The average risk of bias score was equal to 20.13 (SD: 4.2).

The most commonly used questionnaires for neuroticism were the NEO-PI and the Eysenck Personality Inventory (Questionnaire). Alexithymia in our sample was assessed more commonly through the TAS-20 and the BVAQ. Genetic association studies evaluating emotional dysregulation used a wider variety of different tools (see Table 6); further considerations on this trait should take into account this variability.

Since GWAS results are too vast to be meaningfully discussed, data with P ≤ 10−8 was given special consideration. This threshold is considered the standard in newer GWAS, despite suggestions to lower it to 10−7 (Chen et al., 2021).

Table 8 contains the questionnaire abbreviations. Risk of bias scores are shown in Supplementary Material S1, Supplemental Digital Content 2, https://links.lww.com/PG/A296.

Table 8 - Questionnaires abbreviations
Abbreviation Trait Questionnaire
NEO-PI-R NEUROTICISM NEO Personality Inventory-Revised
ABV NEUROTICISM Amsterdamse Biografische Vragenslijst
BFI NEUROTICISM Big Five Inventory
EBBFI NEUROTICISM Estonian Brief Big Five Inventory
MPI NEUROTICISM Maudsley Personality Inventory
EPQ NEUROTICISM Eysenck Personality Questionnaire
EPQ-R NEUROTICISM Eysenck Personality Questionnaire-Revised
DPQ NEUROTICISM Dutch Personality Questionnaire
ZKPQ NEUROTICISM Zuckerman-Kuhlman Personality Questionnaire
EPI NEUROTICISM Eysenck Personality Inventory
TPQ NEUROTICISM Temperament Personality Questionnaire
FPI-R NEUROTICISM Freiburg Personality Inventory-Revised
KSP NEUROTICISM Karolinska Scales of Personality
NEO-PI NEUROTICISM NEO Personality Inventory
TAS ALEXITHYMIA Toronto Alexithymia Scale
BVAQ ALEXITHYMIA Bermond–Vorst Alexithymia Questionnaire
SPSS ALEXITHYMIA Schalling-Sifneos Personality Scale
CAS ALEXITHYMIA Childhood Attachment Security
ERC EMOTIONAL DYSREGULATION Emotion Regulation Checklist
STSC EMOTIONAL DYSREGULATION Short Temperament Scale for Child
SEAS EMOTIONAL DYSREGULATION Self-report Emotional Ability Scale
STAI-S EMOTIONAL DYSREGULATION State form of the State-Trait Anxiety Inventory
ASQ EMOTIONAL DYSREGULATION Affective Style Questionnaire
CERQ EMOTIONAL DYSREGULATION Cognitive Emotion Regulation Questionnaire
PAI-BOR EMOTIONAL DYSREGULATION Personality Assessment Inventory-Borderline Scale
BIRD EMOTIONAL DYSREGULATION Behavioral Indicator of Resilience to Distress


In order to treat the topics in a hierarchical fashion, we decided to prioritize describing results concerning genes that were studied in 10 or more genetic association analyses in their own category. In the successive sections, we proceeded to explore the associations between neuroticism and less studied genes, and finally to discuss the possible genetic basis of the remaining traits.

Neuroticism: SLC6A4, COMT, MAO-A and BDNF

According to the results of our systematic review, no solid association seemed to emerge between neuroticism and these very thoroughly studied genes (Mandelli and Serretti, 2013). These genes have understandably been at the epicenter of scientific attention since the beginning of genetic research in psychiatry (Collier et al., 1996; Eley et al., 2003; Strauss et al., 2004) because of their hypothetical and plausible importance in brain function, especially regarding cortical networks (Matsumoto et al., 2003; Martinowich et al., 2007; Alia-Klein et al., 2008), since their respective proteins are involved in basic neurotransmission and, most importantly, in what was currently believed to be the main mechanism of action of many drugs such as antidepressants and antipsychotics (Sundaram and Mahajan, 1980; Meltzer, 1991).

Despite no meta-analysis being carried out, it is possible to state that these genes might not have a strong connection with neuroticism. Most of the papers found no association; however, in some studies, despite no direct association, these genes were found to significantly increase neuroticism scores when combined with several moderating factors such as sex, sociodemographic status and other secondary factors such as cluster C personality disorder diagnosis (Jacob et al., 2004), meditation practice (Jung et al., 2016) and alcohol abuse (Lovallo et al., 2014). In some cases (Brummett et al., 2003; Sen et al., 2004; Kotyuk et al., 2015; Chang et al., 2017), conflicting evidence emerged regarding which of the two alleles is involved in increasing risk of high neuroticism scores, further weakening the potential connection between these alleles and neuroticism.

As will be more thoroughly discussed further on, no GWAS found any link between these four genes and neuroticism, further weakening their potential in moderating neuroticism.

Neuroticism: other genes and genome-wide association study

Overall, more than 60 other genes were studied, most of them in single studies. Thirty-six of them were significantly associated with neuroticism (a full list of these genes can be found in Supplementary Materials, Supplemental Digital Content 1, https://links.lww.com/PG/A295). Some of these genes are conventionally connected in some fashion to brain function, such as the 5-HTR1A and 2A genes and DRD2, DRD3, DRD4 (Missale et al., 1998; Pytliak et al., 2011); others are transcription factors, adherence proteins or do not have a known function in the nervous system.

GWASs point towards a somewhat similar direction. Most of the studies found associations with intronic or even intergenic noncoding regions (see Supplementary Materials, Supplemental Digital Content 1, https://links.lww.com/PG/A295). This was to be expected, given that the majority of DNA sequences are represented by such regions (Francis and Wörheide, 2017); moreover, such regions are hypothesized to have a regulatory function on translated sequences. This can happen through several different mechanisms. There is growing evidence that intergenic regions might regulate chromatin remodeling (Mayer et al., 2006; Romanowska and Joshi, 2019) and act as enhancers (Ransohoff et al., 2018), thus allowing fine-tuning of more nuanced transcriptional equilibriums as compared to exons.

Most of the GWAS acquired some of their data from the same original dataset, the UK Biobank; as the Biobank was updated, though, the sample increased constantly in numbers. Moreover, several studies employed very interesting nonstandard statistical techniques, which show great promise. Multitrait analysis of GWAS (a variation of standard GWAS in which data on several traits is analyzed jointly in order to maximize detection rate), methylation analysis and pathway analysis are all helpful tools in order to increase both the precision and the scope of GWAS results.

Through pathway analysis, L1CAM, an intercellular signaling adhesion protein, was found to be implicated in increasing neuroticism (Kim et al., 2015). DCAF5 (Hill et al., 2020), coding for a protein involved in ubiquitin function regulation, is also linked to neuroticism scores. In the same study (Kim et al., 2015), another interesting association was PAX6, an embrional transcription factor. It is worth noting that, similarly to what was argued in the above paragraph, exons with regulatory functions on other sequences or biochemical mechanisms tend to be the most common findings when searching for gene-environment associations in the field of psychiatry. As further proof to this statement, polymorphisms in RBFOX1, a splicing-regulating protein, have been replicated in multiple GWAS (Okbay et al., 2016; Luciano et al., 2018; Nagel et al., 2018,2020); variations in LINC00461, a noncoding RNA involved in miRNA and siRNA regulations, are as well a replicated finding (Okbay et al., 2016; Luciano et al., 2018; Nagel et al., 2018; Turley et al., 2018; Hill et al., 2020).

An association was found with two distinct chromosomal inversions (respectively on chromosomes 8 and 17) (Okbay et al., 2016). The exact mechanism by which these chromosomal alterations affect neuroticism is not clear. Widespread regulatory mechanisms disruption and alteration in 3D chromatin structure are a possible hypothesis; Okbay et al. (2016) suggest that the inversion might relocate some crucial regulatory regions.

A solid association can be assumed for CRHR1, since it was found in two GWAS and several genetic association studies. CRHR1 is the gene coding for the corticotropin-releasing factor receptor. As such, it is a key component of stress reaction and cortisol homeostasis. This receptor is also present in the brain and has been connected to satiety feelings (Tu et al., 2007) and depressive and anxiety symptoms (Rogers et al., 2013). No data could be found in literature regarding the exact effect of the variants linked to neuroticism; assuming that these variants decrease the efficacy of CRHR1 receptor, we can hypothesize that this mutation might lead to a reduction of hypothalamic control on cortisol production. A more direct mechanism can also be mentioned; several CRHR1 polymorphisms (not the one found in this review, though) were associated with cortisol reactivity in children (Sheikh et al., 2013).

Several other genes were identified in multiple GWAS. Among these, many have important roles in regulating the neural progenitors migration, such as deleted in colorectal cancer (DCC)(Okbay et al., 2016; Nagel et al., 2018; Turley et al., 2018; Hill et al., 2020), XKR6 (Okbay et al., 2016; Luciano et al., 2018; Hill et al., 2020) and transcription factor 4 (TCF4) (Okbay et al., 2016; Luciano et al., 2018; Nagel et al., 2018; Hill et al., 2020). DCC has also been established as a gene involved in increased impulsivity in children (Jiang et al., 2015) as well as colon cancer risk (Berke, 2018). Other genes have a less clear link to psychopathology, such as MSRA, coding for a protein involved in free-radicals metabolism (Okbay et al., 2016; Luciano et al., 2018; Nagel et al., 2018).

One of the most interesting gene is DRD2; despite mixed results among candidate-gene association studies, with positive association (Wacker et al., 2005; Jutras-Aswad et al., 2012; Grzywacz et al., 2020; Suchanecka et al., 2020) outweighing the null hypothesis (Hibino et al., 2006; Pełka-Wysiecka et al., 2012), GWAS studies replicated several times the finding of its association with neuroticism (Okbay et al., 2016; Luciano et al., 2018; Nagel et al., 2018,2020; Turley et al., 2018; Hill et al., 2020). As mentioned previously, the DRD2 gene codes for a crucial dopamine receptor, currently regarded as being one of the main target of antipsychotics medications.


Data on alexithymia are sparse and less comprehensive compared with neuroticism. Thus, it is not possible to extract conclusive results on the subject. On the other hand, the assessment of alexithymia is extremely homogeneous, as nearly all included studies employed the TAS-20 questionnaire. Some relevant results can nevertheless be extracted.

Interestingly, SLC6A4 association with alexithymia emerged in two studies (Kano et al., 2012; Terock et al., 2018). Moreover, the risk factor was the short variant, which is commonly thought as having an influence on psychopathology, especially in the depression and anxiety spheres (Juhasz et al., 2015). Thus, more data on this peculiar gene-trait association are warranted and needed. Though, it must be underlined that three other studies found no association between SLC6A4 and alexithymia.

Other intriguing associations are those with some chromosomal abnormalities such as Turner and Klinefelter syndromes. Increased psychiatric burden is not a novelty in these syndromes.

For example, there is evidence of higher levels of alexithymia in Turner syndrome if compared with Noonan syndrome and healthy controls (Roelofs et al., 2015).

Other studies concerning Klinefelter syndrome pointed out higher levels of psychological distress, such as depression, paranoid ideation, phobias, psychoticism and obsessive thoughts, and a central role of alexithymia in the development of these aspects (Skakkebæk et al., 2018; Giagulli et al., 2019; van Rijn and Swaab, 2020; Fabrazzo et al., 2021). It is well known in current literature that Klinefelter syndrome might also predispose to the development of maladaptive psychological constructs, such as obsessive-compulsive symptoms associated with lower total, verbal and performance IQ scores, although there is no clear evidence on etiopathological process and if these symptoms are due to genetic makeup or environment and social stigma (Fisher et al., 2015).

These syndromes are known to be associated with a variable degree of social functioning impairment (van Rijn et al., 2018); it is, therefore, worth considering that the areas of performance more commonly affected might predispose to a specific personality trait (with the genetic footprint as a unifying mark).

Noonan syndrome is a cluster of monogenic conditions involving several genes in the RAS-MAPK pathway (PTPN11, SOS1, SHOC2, MAP2K1/2 and KRAS in the included paper).

Also, patients with Noonan syndrome showed higher levels of introversion, alexithymia, anxiety and depression, which may predispose to internalizing problems (Roelofs et al., 2015; Roelofs et al., 2020).

There is also evidence that global and social functioning is negatively correlated with family quality of life and a negative environment (neglect) (Davico et al., 2022), pointing out that environmental factors, in this case, play a relevant role.

A single GWAS was found studying alexithymia (Mezzavilla et al., 2015). Interestingly, this study found several exonic associations: TMEM88B (a transmembrane protein, most likely involved in intercellular signaling), ABCB4 [a transporter protein that is linked to some forms of cancer and multidrug resistances (Nayagam et al., 2020, p. 1)], TP53AIP1 (whose protein is part of the p53 pathway) and ARHGAP32 from the Rho G protein pathway. All of these proteins have very indirect known effects on synapses; two of them, namely, ABCB4 and TP53AIP1, might be involved in neurogenesis of the Novo neurons or in organizing cortical architecture.

Emotion dysregulation

ED assessment in the included studies was far from homogenous (see Table 6 and Introduction section). Evidence drawn from this review must, therefore, be carefully evaluated taking into consideration this fact.

SLC6A4 was the most represented among genes investigated regarding ED. Some theoretical models were proposed in 2007 (Canli and Lesch, 2007) trying to link neuroscience evidence with the genetic data available at the time. The main idea was that SLC6A4 functional variants might induce the amygdala nuclei to be more or less reactive to external stimuli, thus inducing a stronger or weaker emotional response according to the polymorphism. Since our review did not focus on endophenotypes but rather on a more direct association with the trait of interest, we can not undermine or prove such hypothesis. Seven gene-association studies were found regarding SLC6A4 and its relation with ED (mostly in children and adolescents, Table 6); four supported the null hypothesis (Jorm et al., 1998; Kochanska et al., 2009; Weiss et al., 2014; Noroña et al., 2018), whereas two reported an association with the short allele and one reported an association with a polymorphism (rs4680) (Murakami et al., 2009; Amstadter et al., 2012; Viddal et al., 2017). Moreover, GWAS studies on ED did not report association with SLC6A4 (more details in later paragraphs).

Two studies found associations with COMT (only in specific subscales) (Weiss et al., 2014; Amstadter et al., 2012).

An association with the oxytocin receptor was found among a large sample of female children (Byrd et al., 2021). In fact, it is not unreasonable to assume that such a gene might have psychological and psychiatric implications. Interestingly, oxytocin blood and brain level seem to be connected to both prosocial behavior and anger reactions (Aragón et al., 2015; Byrd et al., 2021) and, most importantly in this context, to empathy (Barchi-Ferreira and Osório, 2021).

Our search provided two GWAS eligible for discussion on ED (see Table 7). Both have relatively small samples. One of them (Powers et al., 2016) found a single association with an intronic regulatory region of ILR2A, the gene coding for the interleukin 2A receptor. There is also other evidence linking this receptor to psychiatric conditions in general (Nässberger and Träskman-Bendz, 1993; Rapaport and Stein, 1994) and even directly to alexithymia (Gil et al., 2007; De Berardis et al., 2014). A plausible explanation as to why an interleukin gene could potentially have an impact on personality can be hypothesized through microglia activity in synaptic pruning and modulation in general. The importance of these often neglected cells in brain circuitry homeostasis has already been proven in several neurologic conditions such as Alzheimer's and multiple sclerosis (Augusto-Oliveira et al., 2019; Li et al., 2022) and even in psychotic disorders (Germann et al., 2021). It is, therefore, not unreasonable to assume that interleukin 2A might influence microglia actions on synaptic remodeling and thus affect personality.


Several factors must be accounted for when proposing an interpretation of our results. The diverse nature of assessment tools increases potential biases; a more standard approach in order to measure under-investigated traits such as ED is warranted. An example of such an attitude can be seen in alexithymia research, with the TAS-20 widely being recognized as the main questionnaire.

Another limitation is that most of the studies reviewed did not explain how the study size was arrived at: the reason for this lack of conformity probably lies in the fact that the aforementioned studies did not include a power analysis in their design. Furthermore, characteristics of study participants, such as demographics and social information, were not provided in a majority of the selected studies.


DNA is mostly made of such apparently ‘junk’ regions; as research in genomics and proteomics advances, though, more and more evidences are mounting up to prove the crucial role that intronic and intergenic regions actually have in transcriptional regulation, splicing, chromatin density regulation, methylation and finer modulation mechanisms.

In fact, it could even be hypothesized that the ‘major’ receptor genes are too widespread among the brain, and thus, a mutation in such genes might prove to be too constraining to effectively influence personality and other more subtle psychological traits. On the other hand, a neuroscientific model taking into account millions of base pairs scattered across all chromosomes and constantly influencing both exon and each other’s activity might constitute a better framework and foundation to better understand the way the human brain works. This point of view also has a stronger phylogenetic basis as compared with a model that only encompasses few loci; in fact, having a larger portion of DNA devoted to fine regulation and modulation of brain function allows evolutionary mechanisms more room to act and apply selective pressure (be it positive or negative) that would in turn influence the architecture of a complex organ such as a brain.

This theoretical approach is supported by GWAS results in general, and by GWAS results in neuroticism especially. As detailed in the Discussion section, even when accounting only exonic mutations, most of these affect regulatory and transcriptional proteins (i.e. LINC00461, RBFOX1 and L1CAM) rather than, for example, ion channels or receptors. Evaluating the biochemical impact of such proteins is a complex endeavor that GWAS studies alone cannot fully address; nevertheless, such studies can inform the direction of protein-functionality studies.

Key neurodevelopmental proteins are also potentially involved in the neuroticism pathogenesis, as pointed out by polymorphisms in genes such as DCC, XKR6 and TCF4. Scientific literature, in fact, supports the hypothesis that neuroticism’s phenotype might develop quite early in life (Zupančič and Kavčič, 2013; Ask et al., 2021). Brain structure differences in high neuroticism children, namely in several whole-brain parameters as well as the prefrontal, occipital and lateral temporal cortex (Restrepo-Lozano et al., 2022) have also been reported, despite polygenic risk score associations being inconclusive.

Even though the majority of findings regarded nonconding regions or regulatory exons, GWAS on neuroticism identified significantly and replicated polymorphisms in two key brain receptors: CRHR1 and DRD2. These findings provide an interesting direction for future research, as these receptors’ function is relatively well-known in the brain (Rogers et al., 2013; Berke, 2018).

Little GWAS data are currently available on alexithymia and emotional dysregulation; more research is needed in this area, as the data currently available already yielded some interesting results (TMEM88B, ABCB4 and TP53AIP1 for alexithymia, and ILR2A for emotional dysregulation). Since the studies had small samples for GWAS standards (Hong and Park, 2012; Haram et al., 2014; Powers et al., 2016; Heilbronner et al., 2021) it is likely that more associations could be detected in the future.

Neuroticism, alexithymia and emotional dysregulation constitute key concepts both in psychology research and clinical practice among psychiatrists. These traits influence treatment outcome and prognosis from a variety of directions: therapeutic alliance, compliance with medication and social functioning. Being this the case, understanding their etiopathology and genesis is of crucial importance. Clearly, as is often the case in psychiatry and brain research, genetic factors cannot fully explain the variability of the phenomena by themselves; the environment must play a key role as well. Nevertheless, a full understanding of the genetic side of the coin is necessary and might have huge clinical implications, both directly and indirectly. Genetic panels predicting psychopathological risk might be developed, and pharmaceutical research can and will benefit greatly from a deeper knowledge of these genetic mechanisms. Such mechanisms can be unveiled through additional research, especially in the form of GWAS.


G.P.M. conceived the study, with the coordination offered by G.C., E.C and E. R. for the study design. G.P.M. designed the search algorithm, with the support of. E.C., O.B.B. and V.P.; G.P.M., O.B.B, B.B. and V.P. collected the data and performed the screening process. All authors contributed to the interpretation of the studies and to the synthesis of results. The first draft was written by G.P.M, V.P., B.B. and O.B.B. under the supervision of G.C., V.B., S.S., B.N. and V.R.; the final manuscript was approved by all the authors.

Protocol and registration: methods of the analysis and inclusion criteria were specified in advance and documented in a protocol. The protocol, published in advance, can be retrieved as Prospero ID CRD42021267732.

Availability of data, code and other materials: the database of the studies, with the extracted data items, can be shared upon reasonable request to the corresponding author.

Conflicts of interest

There are no conflicts of interest.


10 years of GWAS discovery: biology, function, and translation - PubMed. https://pubmed.ncbi.nlm.nih.gov/28686856/. [Accessed 19 March 2022]
Alia-Klein N, Goldstein RZ, Kriplani A, Logan J, Tomasi D, Williams B, et al. (2008). Brain monoamine oxidase A activity predicts trait aggression. J Neurosci 28:5099–5104.
Amin N, Schuur M, Gusareva ES, Isaacs A, Aulchenko YS, Kirichenko AV, et al. (2012). A genome-wide linkage study of individuals with high scores on NEO personality traits. Mol Psychiatry 17:1031–1041.
Amstadter AB, Daughters SB, Macpherson L, Reynolds EK, Danielson CK, Wang F, et al. (2012). Genetic associations with performance on a behavioral measure of distress intolerance. J Psychiatr Res 46:87–94.
An L, Chen Z, Zhang N, Ren D, Yuan F, Yuan R, et al. (2019). Genetic association between CELF4 rs1557341 polymorphism and neuroticism in Chinese Han population. Psychiatry Res 279:138–139.
Antypa N, Van der Does AJW (2010). Serotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression. Genes Brain Behav 9:615–620.
Aragam N, Wang KS, Anderson JL, Liu X (2013). TMPRSS9 and GRIN2B are associated with neuroticism: a genome-wide association study in a European sample. J Mol Neurosci 50:250–256.
Aragón OR, Clark MS, Dyer RL, Bargh JA (2015). Dimorphous expressions of positive emotion: displays of both care and aggression in response to cute stimuli. Psychol Sci 26:259–273.
Ask H, Eilertsen EM, Gjerde LC, Hannigan LJ, Gustavson K, Havdahl A, et al. (2021). Intergenerational transmission of parental neuroticism to emotional problems in 8-year-old children: genetic and environmental influences. JCPP Advances 1:e12054.
Augusto-Oliveira M, Arrifano GP, Lopes-Araújo A, Santos-Sacramento L, Takeda PY, Anthony DC, et al. (2019). What do microglia really do in healthy adult brain?. Cells 8:1293E1293.
Ball D, Hill L, Freeman B, Eley TC, Strelau J, Riemann R, et al. (1997). The serotonin transporter gene and peer-rated neuroticism. Neuroreport 8:1301–1304.
Barbato G, Costanzo A, Della Monica C, D’Onofrio P, Cerrato F, De Padova V (2013). Effects of prolonged wakefulness: the role of PERIOD3 genotypes and personality traits. Psychol Rep 113:540–551.
Barchi-Ferreira AM, Osório FL (2021). Associations between oxytocin and empathy in humans: a systematic literature review. Psychoneuroendocrinology 129:105268.
Bayes A, Parker G, McClure G (2016). Emotional dysregulation in those with bipolar disorder, borderline personality disorder and their comorbid expression. J Affect Disord 204:103–111.
Beem AL, Geus EJ, Hottenga JJ, Sullivan PF, Willemsen G, Slagboom PE, Boomsma DI (2006). Combined linkage and association analyses of the 124-bp allele of marker D2S2944 with anxiety, depression, neuroticism and major depression. Behav Genet 36:1.
Belonogova NM, Zorkoltseva IV, Tsepilov YA, Axenovich TI (2021). Gene-based association analysis identifies 190 genes affecting neuroticism. Sci Rep 11:2484.
Berke JD (2018). What does dopamine mean? Nat Neurosci 21:787–793.
Bîlc MI, Vulturar R, Chiș A, Buciuman M, Nuţu D, Bunea I, et al. (2018). Childhood trauma and emotion regulation: the moderator role of BDNF Val66Met. Neurosci Lett 685:7–11.
Bizaoui V, Gage J, Brar R, Rauen KA, Weiss LA (2018). RASopathies are associated with a distinct personality profile. Am J Med Genet B Neuropsychiatr Genet 177:434–446.
Boomsma DI, Helmer Q, Nieuwboer HA, Hottenga JJ, de Moor MH, van den Berg SM, et al. (2018). An extended twin-pedigree study of neuroticism in the Netherlands Twin Register. Behav Genet 48:1–11.
Rao S, Broadbear J (2019). Borderline personality disorder and depressive disorder. Australas Psychiatry 27:573–577.
Boscarino JA, Erlich PM, Hoffman SN, Zhang X (2012). Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment. Neuropsychiatr Dis Treat 8:131–139.
Bradley B, DeFife JA, Guarnaccia C, Phifer J, Fani N, Ressler KJ, et al. (2011). Emotion dysregulation and negative affect: association with psychiatric symptoms. J Clin Psychiatry 72:685–691.
Brummett BH, Siegler IC, McQuoid DR, Svenson IK, Marchuk DA, Steffens DC (2003). Associations among the NEO Personality Inventory, revised and the serotonin transporter gene-linked polymorphic region in elders: effects of depression and gender. Psychiatr Genet 13:13–18.
Burgin CJ, Brown LH, Royal A, Silvia PJ, Barrantes-Vidal N, Kwapil TR (2012). Being with others and feeling happy: emotional expressivity in everyday life. Pers Individ Dif 53:185–190.
Burmeister M, McInnis MG, Zöllner S (2008). Psychiatric genetics: progress amid controversy. Nat Rev Genet 9:527–540.
Byrd AL, Tung I, Manuck SD, Vine V, Horner M, Hipwell AE, et al. (2021). An interaction between early threat exposure and the oxytocin receptor in females: disorder-specific versus general risk for psychopathology and social-emotional mediators. Dev Psychopathol 33:4.
Cai RY, Richdale AL, Uljarević M, Dissanayake C, Samson AC (2018). Emotion regulation in autism spectrum disorder: where we are and where we need to go. Autism Res 11:962–978.
Calboli FCF, Tozzi F, Galwey NW, Antoniades A, Mooser V, Preisig M, et al. (2010). A genome-wide association study of neuroticism in a population-based sample. PLoS One 5:e11504.
Canli T, Lesch K-P (2007). Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10:1103–1109.
Carpenter RW, Trull TJ (2013). Components of emotion dysregulation in borderline personality disorder: a review. Curr Psychiatry Rep 15:335.
Chang WH, Lee IH, Chen KC, Chi MH, Chiu N-T, Yao WJ, et al. (2014). Oxytocin receptor gene rs53576 polymorphism modulates oxytocin-dopamine interaction and neuroticism traits–a SPECT study. Psychoneuroendocrinology 47:212–220.
Chang C-C, Chang H-A, Fang W-H, Chang T-C, Huang S-Y (2017). Gender-specific association between serotonin transporter polymorphisms (5-HTTLPR and rs25531) and neuroticism, anxiety and depression in well-defined healthy Han Chinese. J Affect Disord 207:422–428.
Chang H-A, Fang WH, Liu YP, Tzeng NS, Shyu JF, Wan FJ, et al. (2020). Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder. J Psychiatry Neurosci 45:379–386.
Chapman BP, Benedict RHB, Lin F, Roy S, Porteinsson A, Szigeti K, et al. (2018). Apolipoprotein E genotype impact on memory and attention in older persons: the moderating role of personality phenotype. Int J Geriatr Psychiatry 33:332–339.
Chen Z, Boehnke M, Wen X, Mukherjee B (2021). Revisiting the genome-wide significance threshold for common variant GWAS. G3 Bethesda Md 11:jkaa056.
Chong A, Chew SH, Lai PS, Ebstein RP, Gouin J-P (2019). The role of the oxytocin-neurophysin I gene in contributing to human personality traits promoting sociality. Int J Psychophysiol 136:81–86.
Close Kirkwood S, Siemers E, Viken RJ, Hodes ME, Conneally PM, Christian JC, et al. (2002). Evaluation of psychological symptoms among presymptomatic HD gene carriers as measured by selected MMPI scales. J Psychiatr Res 36:377–382.
Cole PM (2014). Moving ahead in the study of the development of emotion regulation. Int J Behav Dev 38:203–207.
Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D, et al. (1996). A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460.
Collins AL, Sullivan PF (2013). Genome-wide association studies in psychiatry: what have we learned?. Br J Psychiatry 202:1–4.
Connor KM, Davidson JRT (2003). Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety 18:76–82.
Criado JR, Gizer IR, Edenberg HJ, Ehlers CL (2014). CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women. Twin Res Hum Genet 17:80–88.
Ayinde OO, Gureje O (2021). Cross-cultural applicability of ICD-11 and DSM-5 personality disorder. Curr Opin Psychiatry 34:70–75.
Dar-Nimrod I, Chapman BP, Robbins JA, Porsteinsson A, Mapstone M, Duberstein PR (2012). Gene by neuroticism interaction and cognitive function among older adults. Int J Geriatr Psychiatry 27:1147–1154.
Davico C, Borgogno M, Campagna F, D'Alessandro R, Ricci F, Amianto F, et al. (2022). Psychopathology and adaptive functioning in children, adolescents, and young adults with Noonan Syndrome. J Dev Behav Pediatr 43:e87–e93.
Deary IJ, Battersby S, Whiteman MC, Connor JM, Fowkes FG, Harmar A (1999). Neuroticism and polymorphisms in the serotonin transporter gene. Psychol Med 29:735–739.
De Berardis D, Conti C, Iasevoli F, Valchera A, Fornaro M, Cavuto M, et al. (2014). Alexithymia and its relationships with acute phase proteins and cytokine release: an updated review. J Biol Regul Homeost Agents 28:795–799.
Shaw P, Stringaris A, Nigg J, Leibenluft E (2014). Emotion dysregulation in attention deficit hyperactivity disorder. Am J Psychiatry 171:276–293.
Goerlich KS. (2018). The multifaceted nature of alexithymia–a neuroscientific perspective. Front Psychol 9:1614.
Widiger TA, Oltmanns JR (2007). Neuroticism is a fundamental domain of personality with enormous public health implications. World Psychiatry 16:144.
Montagne B, Kessels RP, De Haan EH, Perrett DI (2007). The emotion recognition task: a paradigm to measure the perception of facial emotional expressions at different intensities. Percept Motor Skill 104:589–598.
Sifneos PE (1973). The prevalence of ‘Alexithymic’ characteristics in psychosomatic patients. Psychother Psychosom 22:255–262.
Silverman MH, Wilson S, Ramsay IS, Hunt RH, Thomas KM, Krueger RF, et al. (2019). Trait neuroticism and emotion neurocircuitry: functional magnetic resonance imaging evidence for a failure in emotion regulation. Dev Psychopathol 31:1085–1099.
van den Oord EJCG, Kuo P-H, Hartmann AM, Webb BT, Möller H-J, Hettema JM, et al. (2008). Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Arch Gen Psychiatry 65:1062–1071.
DeYoung CG, Cicchetti D, Rogosch FA (2011). Moderation of the association between childhood maltreatment and neuroticism by the corticotropin-releasing hormone receptor 1 gene. J Child Psychol Psychiatry 52:898–906.
Dragan W, Oniszczenko W (2006). Association of a functional polymorphism in the serotonin transporter gene with personality traits in females in a Polish population. Neuropsychobiology 54:45–50.
Du L, Bakish D, Hrdina PD (2000). Gender differences in association between serotonin transporter gene polymorphism and personality traits. Psychiatr Genet 10:159–164.
Dvir Y, Ford JD, Hill M, Frazier JA (2014). Childhood maltreatment, emotional dysregulation, and psychiatric comorbidities. Harv Rev Psychiatry 22:149–161.
Eley TC, Tahir E, Angleitner A, Harriss K, McClay J, Plomin R, et al. (2003). Association analysis of MAOA and COMT with neuroticism assessed by peers. Am J Med Genet B Neuropsychiatr Genet 120B:90–96.
Ellis JA, Olsson CA, Moore E, Greenwood P, Van De Ven MOM, Patton GC (2011). A role for the DRD4 exon III VNTR in modifying the association between nicotine dependence and neuroticism. Nicotine Tob Res 13:64–69.
Escamilla MA, Zavala JM (2008). Genetics of bipolar disorder. Dialogues Clin Neurosci 10:141–152.
Eysenck HJ (1952). The scientific study of personality. Br J Stat Psychol 6:44–52.
Fabrazzo M, Accardo G, Abbondandolo I, Goglia G, Esposito D, Sampogna G, et al. (2021). Quality of life in Klinefelter patients on testosterone replacement therapy compared to healthy controls: an observational study on the impact of psychological distress, personality traits, and coping strategies. J Endocrinol Invest 44:1053–1063.
Fan Q, Wang W, Hao J, He A, Wen Y, Guo X, et al. (2017). Integrating genome-wide association study and expression quantitative trait loci data identifies multiple genes and gene set associated with neuroticism. Prog Neuropsychopharmacol Biol Psychiatry 78:149–152.
Fiocco AJ, Joober R, Poirier J, Lupien S (2007). Polymorphism of the 5-HT(2A) receptor gene: association with stress-related indices in healthy middle-aged adults. Front Behav Neurosci 1:3.
Fiocco AJ, Nair NPV, Schwartz G, Kin FNY, Joober R, Poirier J, et al. (2009). Influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on stress markers in older adults: a 3-year study. Neurobiol Aging 30:1001–1005.
Fisher AD, Castellini G, Casale H, Fanni E, Bandini E, Campone B, et al. (2015). Hypersexuality, paraphilic behaviors, and gender dysphoria in individuals with Klinefelter’s syndrome. J Sex Med 12:2413–2424.
Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF (1999). Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol Psychiatry 4:93–96.
Francis WR, Wörheide G (2017). Similar ratios of introns to intergenic sequence across animal genomes. Genome Biol Evol 9:1582–1598.
Fullerton J, Cubin M, Tiwari H, Wang C, Bomhra A, Davidson S, et al. (2003). Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am J Hum Genet 72:879–890.
Gale CR, Hagenaars SP, Davies G, Hill WD, Liewald DCM, Cullen B, et al.; International Consortium for Blood Pressure GWAS, CHARGE Consortium Aging and Longevity Group (2016). Pleiotropy between neuroticism and physical and mental health: findings from 108 038 men and women in UK Biobank. Transl Psychiatry 6:e791–e791.
Garke M, Isacsson NH, Sörman K, Bjureberg J, Hellner C, Gratz KL, et al. (2021). Emotion dysregulation across levels of substance use. Psychiatry Res 296:113662.
Gatt JM, Clark CR, Kemp AH, Liddell BJ, Dobson-Stone C, Kuan SA, et al. (2007). A genotype-endophenotype-phenotype path model of depressed mood: integrating cognitive and emotional markers. J Integr Neurosci 6:75–104.
Gelernter J, Kranzler H, Coccaro EF, Siever LJ, New AS (1998). Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects. Am J Psychiatry 155:1332–1338.
Germann M, Brederoo SG, Sommer IEC (2021). Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders. Curr Opin Psychiatry 34:222–227.
Giagulli VA, Campone B, Castellana M, Salzano C, Fisher AD, de Angelis C, et al.; On Behalf of the Klinefelter ItaliaN Group King (2019). Neuropsychiatric aspects in men with Klinefelter syndrome. Endocr Metab Immune Disord Drug Targets 19:109–115.
Gil FP, Nickel M, Ridout N, Schwarz MJ, Schoechlin C, Schmidmaier R (2007). Alexithymia and interleukin variations in somatoform disorder. Neuroimmunomodulation 14:235–242.
Gillespie NA, Zhu G, Evans DM, Medland SE, Wright MJ, Martin NG (2008). A genome-wide scan for Eysenckian personality dimensions in adolescent twin sibships: psychoticism, extraversion, neuroticism, and lie. J Pers 76:1415–1446.
Glocke M, Lang F, Schaeffeler E, Lang T, Schwab M, Lang UE (2013). Impact of vitamin D receptor VDR rs2228570 polymorphism in oldest old. Kidney Blood Press Res 37:311–322.
Gong P, Liu J, Li S, Zhou X (2014). Serotonin receptor gene (5-HT1A) modulates alexithymic characteristics and attachment orientation. Psychoneuroendocrinology 50:274–279.
Gratz KL, Roemer L (2004). Multidimensional assessment of emotion regulation and dysregulation: development, factor structure, and initial validation of the difficulties in emotion regulation scale. J Psychopathol Behav Assess 26:41–54.
Gratz KL, Roemer L (2008). ‘The relationship between emotion dysregulation and deliberate self-harm among female undergraduate students at an urban commuter university’. Cogn Behav Ther 37:14–25.
Grazioplene RG, Deyoung CG, Rogosch FA, Cicchetti D (2013). A novel differential susceptibility gene: CHRNA4 and moderation of the effect of maltreatment on child personality. J Child Psychol Psychiatry 54:872–880.
Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, et al. (2000). Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 96:202–216.
Grzywacz A, Suchanecka A, Chmielowiec J, Chmielowiec K, Szumilas K, Masiak J, et al. (2020). Personality traits or genetic determinants-which strongly influences e-cigarette users?. Int J Environ Res Public Health 17:365E365.
Gustavsson JP, Nöthen MM, Jönsson EG, Neidt H, Forslund K, Rylander G, et al. (1999). No association between serotonin transporter gene polymorphisms and personality traits. Am J Med Genet 88:430–436.
Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Müller J, Zeng Y, et al. (2007). Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. Int J Neuropsychopharmacol 10:309–320.
Halldorsdottir T, de Matos APS, Awaloff Y, Arnarson E, Craighead WE, Binder EB (2017). FKBP5 moderation of the relationship between childhood trauma and maladaptive emotion regulation strategies in adolescents. Psychoneuroendocrinology 84:61–65.
Ham BJ, Lee MS, Lee YM, Kim MK, Choi MJ, Oh KS, et al. (2005). Association between the catechol O-methyltransferase Val108/158Met polymorphism and alexithymia. Neuropsychobiology 52:1513.
Haram M, Tesli M, Dieset I, Steen NE, Røssberg JI, Djurovic S, et al. (2014). An attempt to identify single nucleotide polymorphisms contributing to possible relationships between personality traits and oxytocin-related genes. Neuropsychobiology 69:25–30.
Harro J, Merenäkk L, Nordquist N, Konstabel K, Comasco E, Oreland L (2009). Personality and the serotonin transporter gene: associations in a longitudinal population-based study, Biol Psychol 81:9–13.
Hawn SE, Overstreet C, Stewart KE, Amstadter AB (2015). Recent advances in the genetics of emotion regulation: a review. Curr Opin Psychol 3:108–116.
Heck A, Lieb R, Unschuld PG, Ellgas A, Pfister H, Lucae S, et al. (2008). Evidence for associations between PDE4D polymorphisms and a subtype of neuroticism. Mol Psychiatry 13:831–832.
Heilbronner U, Papiol S, Budde M, Andlauer TFM, Strohmaier J, Streit F, et al. (2021). ‘The Heidelberg Five’ personality dimensions: genome-wide associations, polygenic risk for neuroticism, and psychopathology 20 years after assessment. Am J Med Genet B Neuropsychiatr Genet 186:77–89.
Hemming L, Haddock G, Shaw J, Pratt D (2019). Alexithymia and its associations with depression, suicidality, and aggression: an overview of the literature. Front Psychiatry 10:203.
Henderson AS, Korten AE, Jorm AF, Jacomb PA, Christensen H, Rodgers B, et al. (2000). COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders. Am J Med Genet 96:102–107.
Henriksen MG, Nordgaard J, Jansson LB (2017). Genetics of schizophrenia: overview of methods, findings and limitations. Front Hum Neurosci 11:322.
Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJCG, Kendler KS, et al. (2006). Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 11:752–762.
Hettema JM, An SS, van den Oord EJCG, Neale MC, Kendler KS, Chen X (2008). Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 147B:661–666.
Hettema JM, An S-S, van den Oord EJCG, Neale MC, Kendler KS, Chen X (2009a). Association study of CREB1 with major depressive disorder and related phenotypes. Am J Med Genet B Neuropsychiatr Genet 150B:1128–1132.
Hettema JM, van den Oord EJCG, An S-S, Kendler KS, Chen X (2009b). Follow-up association study of novel neuroticism gene MAMDC1. Psychiatr Genet 19:213–214.
Hettema JM, An S-S, van den Oord EJCG, Neale MC, Kendler KS, Chen X (2013). Genetic association between RGS1 and internalizing disorders. Psychiatr Genet 23:56–60.
Hettema JM, Chen X, Sun C, Brown TA (2015). Direct, indirect and pleiotropic effects of candidate genes on internalizing disorder psychopathology. Psychol Med 45:2227–2236.
Hibino H, Tochigi M, Otowa T, Kato N, Sasaki T (2006). No association of DRD2, DRD3, and tyrosine hydroxylase gene polymorphisms with personality traits in the Japanese population. Behav Brain Funct 2:32.
Hill WD, Weiss A, Liewald DC, Davies G, Porteous DJ, Hayward C, et al. (2020). Genetic contributions to two special factors of neuroticism are associated with affluence, higher intelligence, better health, and longer life. Mol Psychiatry 25:3034–3052.
Hong EP, Park JW (2012). Sample size and statistical power calculation in genetic association studies. Genomics Inform 10:117–122.
Hoth KF, Paul RH, Williams LM, Dobson-Stone C, Todd E, Schofield PR, et al. (2006). Associations between the COMT Val/Met polymorphism, early life stress, and personality among healthy adults. Neuropsychiatr Dis Treat 2:219–225.
Hou B, Ji L, Chen Z, An L, Zhang N, Ren D, et al. (2020). Role of rs454214 in personality mediated depression and subjective well-being. Sci Rep 10:5702.
Hünnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP (2007). Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology 32:2552–2560.
Iliadis SI, Comasco E, Hellgren C, Kollia N, Sundström Poromaa I, Skalkidou A (2017). Associations between a polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene, neuroticism and postpartum depression. J Affect Disord 207:141–147.
Jacob CP, Strobel A, Hohenberger K, Ringel T, Gutknecht L, Reif A, et al. (2004). Association between allelic variation of serotonin transporter function and neuroticism in anxious cluster C personality disorders. Am J Psychiatry 161:569–572.
Jang KL, Livesley WJ, Vernon PA (1996). Heritability of the big five personality dimensions and their facets: a twin study. J Pers 64:577–591.
Jang KL, Hu S, Livesley WJ, Angleitner A, Riemann R, Ando J, et al. (2001). Covariance structure of neuroticism and agreeableness: a twin and molecular genetic analysis of the role of the serotonin transporter gene. J Pers Soc Psychol 81:295–304.
Jiang HW, Wang J, Li HJ, Peng JK, Gao XP, Chen F (2015). Influence of the DCC gene on proliferation and carcinoembryonic antigen expression in the human colorectal cancer cell line SW1116. Genet Mol Res 14:10273–10280.
Joffe RT, Gatt JM, Kemp AH, Grieve S, Dobson-Stone C, Kuan SA, et al. (2009). Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: implications for depressive illness. Hum Brain Mapp 30:1246–1256.
Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, et al. (1998). An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Mol Psychiatry 3:449–451.
Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, et al. (2000a). Association of a functional polymorphism of the monoamine oxidase A gene promoter with personality and psychiatric symptoms. Psychiatr Genet 10:87–90.
Jorm AF, Prior M, Sanson A, Smart D, Zhang Y, Easteal S (2000b). Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: a longitudinal study from infancy to the mid-teens. Mol. Psychiatry 5:5425.
Juhasz G, Chase D, Pegg E, Downey D, Toth ZG, Stones K, et al. (2009). CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms. Neuropsychopharmacology 34:2019–2027.
Juhasz G, Downey D, Hinvest N, Thomas E, Chase D, Toth ZG, et al. (2010). Risk-taking behavior in a gambling task associated with variations in the tryptophan hydroxylase 2 gene: relevance to psychiatric disorders. Neuropsychopharmacology 35:1109–1119.
Juhasz G, Gonda X, Hullam G, Eszlari N, Kovacs D, Lazary J, et al. (2015). Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors. PLoS One 10:e0116316.
Jung Y-H, Lee US, Jang JH, Kang DH (2016). Effects of mind-body training on personality and behavioral activation and inhibition system according to BDNF Val66Met polymorphism. Psychiatry Investig 13:333–340.
Jurczak A, Szkup M, Wieder-Huszla S, Grzywacz A, Samochowiec A, Karakiewicz B, et al. (2015). The assessment of the relationship between personality, the presence of the 5HTT and MAO-A polymorphisms, and the severity of climacteric and depressive symptoms in postmenopausal women. Arch Womens Ment Health 18:613–621.
Jutras-Aswad D, Jacobs MM, Yiannoulos G, Roussos P, Bitsios P, Nomura Y, et al. (2012). Cannabis-dependence risk relates to synergism between neuroticism and proenkephalin SNPs associated with amygdala gene expression: case-control study. PLoS One 7:e39243.
Kano M, Mizuno T, Kawano Y, Aoki M, Kanazawa M, Fukudo S (2012). Serotonin transporter gene promoter polymorphism and alexithymia. Neuropsychobiology 65:76–82.
Kataja E-L, Leppänen JM, Kantojärvi K, Pelto J, Häikiö T, Korja R, et al. (2020). The role of TPH2 variant rs4570625 in shaping infant attention to social signals. Infant Behav Dev 60:101471.
Kato C, Kakiuchi C, Umekage T, Tochigi M, Kato N, Kato T, Sasaki T (2005). XBP1 gene polymorphism (-116C/G) and personality. Am J Med Genet B Neuropsychiatr Genet 136B:103–105.
Kazantseva AV, Gaysina DA, Faskhutdinova GG, Noskova T, Malykh SB, Khusnutdinova EK (2008). Polymorphisms of the serotonin transporter gene (5-HTTLPR, A/G SNP in 5-HTTLPR, and STin2 VNTR) and their relation to personality traits in healthy individuals from Russia. Psychiatr Genet 18:167–176.
Kazantseva A, Gaysina D, Malykh S, Khusnutdinova E (2011). The role of dopamine transporter (SLC6A3) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms in personality traits. Prog Neuropsychopharmacol Biol Psychiatry 35:1033–1040.
Khan AA, Jacobson KC, Gardner CO, Prescott CA, Kendler KS (2005). Personality and comorbidity of common psychiatric disorders. Br J Psychiatry 186:190–196.
Kim H-N, Roh S-J, Sung YA, Chung HW, Lee J-Y, Cho J, et al. (2013). Genome-wide association study of the five-factor model of personality in young Korean women. J Hum Genet 58:667–674.
Kim H-N, Kim B-H, Cho J, Ryu S, Shin H, Sung J, et al. (2015). Pathway analysis of genome-wide association datasets of personality traits. Genes Brain Behav 14:345–356.
Knowles JB, Kreitman N (1965). The Eysenck Personality Inventory: some considerations. Br J Psychiatry 111:755–759.
Kochanska G, Philibert RA, Barry RA (2009). Interplay of genes and early mother-child relationship in the development of self-regulation from toddler to preschool age. J Child Psychol Psychiatry 50:1331–1338.
Koh MJ, Kim W, Kang JI, Namkoong K, Kim SJ (2015). Lack of association between Oxytocin Receptor (OXTR) gene polymorphisms and alexithymia: evidence from patients with obsessive-compulsive disorder. PLoS One 10: e014316811.
Koh MJ, Kang JI, Namkoong K, Lee SY, Kim SJ (2016). Association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and alexithymia in patients with obsessive-compulsive disorder. Yonsei Med J 57:7213.
Koller G, Bondy B, Preuss UW, Zill P, Soyka M (2006). The C(-1019)G 5-HT1A promoter polymorphism and personality traits: no evidence for significant association in alcoholic patients. Behav. Brain Funct 2:1–6.
Kotyuk E, Duchek J, Head D, Szekely A, Goate AM, Balota DA (2015). A genetic variant (COMT) coding dopaminergic activity predicts personality traits in healthy elderly. Pers Individ Diff 82:61–66.
Kruschwitz JD, Walter M, Varikuti D, Jensen J, Plichta MM, Haddad L, et al. (2015). 5-HTTLPR/rs25531 polymorphism and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus. Brain Struct Funct 220:4.
Kuepper Y, Wielpuetz C, Alexander N, Mueller E, Grant P, Hennig J (2012). 5-HTTLPR S-allele: a genetic plasticity factor regarding the effects of life events on personality?. Genes Brain Behav 11:643–650.
Kuhnen CM, Samanez-Larkin GR, Knutson B (2013). Serotonergic genotypes, neuroticism, and financial choices. PLoS One 8:e54632.
Kurrikoff T, Lesch K-P, Kiive E, Konstabel K, Herterich S, Veidebaum T, et al. (2012). Association of a functional variant of the nitric oxide synthase 1 gene with personality, anxiety, and depressiveness. Dev Psychopathol 24:1225–1235.
Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, et al. (2005). Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI’. Neurosci Lett 391:7–10.
Laas K, Reif A, Kiive E, Domschke K, Lesch KP, Veidebaum T, Harro J (2014). A functional NPSR1 gene variant and environment shape personality and impulsive action: a longitudinal study. J Psychopharmacol 28:227–236.
Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T, et al. (2005). Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 180:95–99.
Larsen IU, Mortensen EL, Vinther-Jensen T, Nielsen JE, Knudsen GM, Vogel A (2016). Personality traits in Huntington’s disease: an exploratory study of gene expansion carriers and non-carriers. Am J Med Genet B Neuropsychiatr Genet 171:1153–1160.
Lehto K, Akkermann K, Parik J, Veidebaum T, Harro J (2013). Effect of COMT Val158Met polymorphism on personality traits and educational attainment in a longitudinal population representative study. Eur Psychiatry 28:492–498.
Lehto K, Vaht M, Mäestu J, Veidebaum T, Harro J (2015). Effect of tryptophan hydroxylase-2 gene polymorphism G-703 T on personality in a population representative sample. Prog Neuropsychopharmacol Biol Psychiatry 57:31–35.
Lehto K, Mäestu J, Kiive E, Veidebaum T, Harro J (2016). BDNF Val66Met genotype and neuroticism predict life stress: a longitudinal study from childhood to adulthood. Eur Neuropsychopharmacol 26:562–569.
Lerman C, Caporaso NE, Audrain J, Main D, Boyd NR, Shields PG (2000). Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence. Mol Psychiatry 5:189–192.
Li X, He L, Liu J, Guo W, Wang Q, Fang P, et al. (2020). The rs6311 of serotonin receptor 2A (5-HT2A) gene is associated with alexithymia and mental health. J Affect Disord 272:277–282.
Li B, Yang W, Ge T, Wang Y, Cui R (2022). Stress induced microglial activation contributes to depression. Pharmacol Res 106145.
Little J, Higgins JPT, Ioannidis JPA, Moher D, Gagnon F, von Elm E, et al.; STrengthening the REporting of Genetic Association Studies (2009). STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med 6:e22.
Lo M-T, Wang Y, Kauppi K, Sanyal N, Fan C-C, Smeland OB, et al. (2017). Modeling prior information of common genetic variants improves gene discovery for neuroticism. Hum Mol Genet 26:4530–4539.
Loo R (1979). A psychometric investigation of the Eysenck Personality Questionnaire. J Pers Assess 43:54–58.
Lovallo WR, Enoch M-A, Yechiam E, Glahn DC, Acheson A, Sorocco KH, et al. (2014). Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns Project. Alcohol Clin Exp Res 38:1575–1581.
Luciano M, Houlihan LM, Harris SE, Gow AJ, Hayward C, Starr JM, et al. (2010). Association of existing and new candidate genes for anxiety, depression and personality traits in older people. Behav Genet 40:518–532.
Luciano M, Huffman JE, Arias-Vásquez A, Vinkhuyzen AA, Middeldorp CM, Giegling I, et al. (2012). Genome-wide association uncovers shared genetic effects among personality traits and mood states. Am J Med Genet B Neuropsychiatr Genet 159B:684–695.
Luciano M, Hagenaars SP, Davies G, Hill WD, Clarke T-K, Shirali M, et al. (2018). Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism. Nat Genet 50:6–11.
Luciano M, Davies G, Summers KM, Hill WD, Hayward C, Liewald DC, et al. (2021). The influence of X chromosome variants on trait neuroticism. Mol Psychiatry 26:483–491.
Luo YLL, Welker KM, Way B, DeWall N, Bushman BJ, Wildschut T, et al. (2019). 5-HTTLPR polymorphism is associated with nostalgia proneness: the role of neuroticism. Soc Neurosci 14:2.
Madsen MK, Mc Mahon B, Andersen SB, Siebner HR, Knudsen GM, Fisher PM (2016). Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism. Soc Cogn Affect Neurosci 11:140–149.
Mandelli L, Serretti A (2013). Gene environment interaction studies in depression and suicidal behavior: an update. Neurosci Biobehav Rev 37(10 Pt 1):2375–2397.
Mandelli L, Marangoni C, Liappas I, Albani D, Forloni G, Piperi C, et al. (2013). Impact of 5-HTTLPR polymorphism on alexithymia in alcoholic patients after detoxification treatment. J Addict Med 7:372–373.
Mannarini S, Balottin L, Toldo I, Gatta M (2016). Alexithymia and psychosocial problems among Italian preadolescents. A latent class analysis approach. Scand J Psychol 57:473–481.
Markus CR (2013). Interaction between the 5-HTTLPR genotype, impact of stressful life events, and trait neuroticism on depressive symptoms in healthy volunteers. Psychiatr Genet 23:108–116.
Markus CR, Capello AEM (2012). Contribution of the 5-HTTLPR gene by neuroticism on weight gain in male and female participants. Psychiatr Genet 22:279–285.
Martinowich K, Manji H, Lu B (2007). New insights into BDNF function in depression and anxiety. Nat Neurosci 10:1089–1093.
Matsumoto M, Weickert CS, Beltaifa S, Kolachana B, Chen J, Hyde TM, et al. (2003). Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia. Neuropsychopharmacology 28:1521–1530.
Mayer C, Schmitz K-M, Li J, Grummt I, Santoro R (2006). Intergenic transcripts regulate the epigenetic state of rRNA genes. Mol Cell 22:351–361.
McCrae RR, Costa PT, Martin TA (2005). The NEO-PI-3: a more readable revised NEO personality inventory, J Pers Assess 84:261–270.
McGuinness LA, Higgins JPT (2021). Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods 12:55–61.
McIntosh AM, Simen AA, Evans KL, Hall J, Macintyre DJ, Blackwood D, et al. (2012). Genetic variation in hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression. Front Genet 3:116.
Meltzer HY (1991). The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17:263–287.
Messina A, Fogliani AM, Paradiso S (2010). Association between alexithymia, neuroticism, and social desirability scores among Italian graduate students. Psychol Rep 107:185–192.
Mezzavilla M, Ulivi S, Bianca ML, Carlino D, Gasparini P, Robino A (2015). Analysis of functional variants reveals new candidate genes associated with alexithymia. Psychiatry Res 227:3632–365.
Michałowska-Sawczyn M, Niewczas M, Król P, Czarny W, Rzeszutko A, Chmielowiec K, et al. (2019). Associations between the dopamine D4 receptor gene polymorphisms and personality traits in elite athletes. Biol Sport 36:365–372.
Middeldorp CM, de Geus EJ, Beem AL, Lakenberg N, Hottenga JJ, Slagboom PE, Boomsma DI (2007). Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression. Behav Genet 37:294–301.
Middeldorp CM, de Geus EJC, Willemsen G, Hottenga JJ, Slagboom PE, Boomsma DI (2010a). The serotonin transporter gene length polymorphism (5-HTTLPR) and life events: no evidence for an interaction effect on neuroticism and anxious depressive symptoms. Twin Res Hum Genet 13:544–549.
Middeldorp CM, Vink JM, Hettema JM, de Geus EJ, Kendler KS, Willemsen G, et al. (2010b). An association between Epac-1 gene variants and anxiety and depression in two independent samples. Am J Med Genet B Neuropsychiatr Genet 153B:214–219.
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998). Dopamine receptors: from structure to function. Physiol Rev 78:189–225.
Montag C, Bleek B, Faber J, Reuter M (2012). The role of the DRD2 C957T polymorphism in neuroticism in persons who stutter and healthy controls. Neuroreport 23:246–250.
Montag C, Eichner M, Markett S, Quesada CM, Schoene-Bake J-C, Melchers M, et al. (2013). An interaction of a NR3C1 polymorphism and antenatal solar activity impacts both hippocampus volume and neuroticism in adulthood. Front Hum Neurosci 7:243.
Morris J, Leung SSY, Bailey MES, Cullen B, Ferguson A, Graham N, et al. (2020). Exploring the role of contactins across psychological, psychiatric and cardiometabolic traits within UK Biobank. Genes 11:1326E1326.
Murakami H, Matsunaga M, Ohira H (2009). Association of serotonin transporter gene polymorphism and emotion regulation. Neuroreport 20:4144.
Nagel M, Watanabe K, Stringer S, Posthuma D, Sluis S. van der (2018). Item-level analyses reveal genetic heterogeneity in neuroticism. Nat Commun 9:905.
Nagel M, Speed D, van der Sluis S, Østergaard SD. (2020). Genome-wide association study of the sensitivity to environmental stress and adversity neuroticism cluster. Acta Psychiatr Scand 141:476–478.
Narita S, Iwahashi K, Nagahori K, Numajiri M, Yoshihara E, Ohtani N, et al. (2015). Analysis of association between norepinephrine transporter gene polymorphisms and personality traits of NEO-FFI in a Japanese population. Psychiatry Investig 12:381–387.
Narita S, Onozawa Y, Yoshihara E, Nishizawa D, Numajiri M, Ikeda K, Iwahashi K (2018). Association between N-methyl-D-aspartate receptor subunit 2B gene polymorphisms and personality traits in a young Japanese population. East Asian Arch Psychiatry 28:45–52.
Nässberger L, Träskman-Bendz L (1993). Increased soluble interleukin-2 receptor concentrations in suicide attempters. Acta Psychiatr Scand 88:48–52.
Nayagam JS, Williamson C, Joshi D, Thompson RJ (2020). Review article: liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1. Aliment Pharmacol Ther 52:1628–1639.
NCT04979507 (2021). Sleep and emotional reactivity in alcohol use disorder. https://clinicaltrials.gov/show/NCT04979507. [Accessed 19 March 2022].
Neale BM, Sullivan PF, Kendler KS (2005). A genome scan of neuroticism in nicotine dependent smokers. Am J Med Genet B Neuropsychiatr Genet 132B:65–69.
Nestor PG, Hasler VC, O’Donovan K, Lapp HE, Boodai SB, Hunter R (2021). In search of positive mental health: personality profiles and genetic polymorphisms. Stress Health 37:310–319.
Noroña AN, Tung I, Lee SS, Blacher J, Crnic KA, Baker BL (2018). Developmental patterns of child emotion dysregulation as predicted by serotonin transporter genotype and parenting. J Clin Child Adolesc Psychol 47(Suppl 1):S354–S368.
Okbay A, Baselmans BML, De Neve J-E, Turley P, Nivard MG, Fontana MA, et al.; LifeLines Cohort Study (2016). Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet 48:624–633.
Olsson CA, Anney RJL, Lotfi-Miri M, Byrnes GB, Williamson R, Patton GC (2005). Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet 15:109–115.
Ormel J, Jeronimus BF, Kotov R, Riese H, Bos EH, Hankin B, et al. (2013). Neuroticism and common mental disorders: meaning and utility of a complex relationship. Clin Psychol Rev 33:686–697.
Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. (2021). PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 372:n160.
Panitz C, Sperl MFJ, Hennig J, Klucken T, Hermann C, Mueller EM (2018). Fearfulness, neuroticism/anxiety, and COMT Val158Met in long-term fear conditioning and extinction. Neurobiol Learn Mem 155:7–20.
Pascual JC, Soler J, Baiget M, Cortés A, Menoyo A, Barrachina J, et al. (2007). Association between the serotonin transporter gene and personality traits in borderline personality disorder patients evaluated with Zuckerman-Zuhlman Personality Questionnaire (ZKPQ). Actas Esp Psiquiatr 35:382–386.
Paulus DJ, Vanwoerden S, Norton PJ, Sharp C (2016). Emotion dysregulation, psychological inflexibility, and shame as explanatory factors between neuroticism and depression. J Affect Disord 190:376–385.
Peciña M, Love T, Stohler CS, Goldman D, Zubieta J-K (2015). Effects of the Mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures. Neuropsychopharmacology 40:957–965.
Pełka-Wysiecka J, Ziętek J, Grzywacz A, Kucharska-Mazur J, Bienkowski P, Samochowiec J (2012). Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 39:40–46.
Persson ML, Wasserman D, Jönsson EG, Bergman H, Terenius L, Gyllander A, et al. (2000). Search for the influence of the tyrosine hydroxylase (TCAT)(n) repeat polymorphism on personality traits. Psychiatry Res 95:1–8.
Petito A, Altamura M, Iuso S, Padalino FA, Sessa F, D'Andrea G, et al. (2016). The relationship between personality traits, the 5HTT polymorphisms, and the occurrence of anxiety and depressive symptoms in Elite Athletes. PLoS One 11:e0156601.
Picardi A, Fagnani C, Gigantesco A, Toccaceli V, Lega I, Stazi MA (2011). Genetic influences on alexithymia and their relationship with depressive symptoms. J Psychosom Res 71:256–263.
Plieger T, Montag C, Felten A, Reuter M (2014). The serotonin transporter polymorphism (5-HTTLPR) and personality: response style as a new endophenotype for anxiety. Int J Neuropsychopharmacol 17:851–858.
Powers A, Cross D, Fani N, Bradley B (2015a). PTSD, emotion dysregulation, and dissociative symptoms in a highly traumatized sample. J Psychiatr Res 61:174–179.
Powers A, Stevens J, Fani N, Bradley B (2015b). Construct validity of a short, self report instrument assessing emotional dysregulation. Psychiatry Res 225:85–92.
Powers A, Almli L, Smith A, Lori A, Leveille J, Ressler KJ, et al. (2016). A genome-wide association study of emotion dysregulation: evidence for interleukin 2 receptor alpha. J Psychiatr Res 83:195–202.
Propper CB, Shanahan MJ, Russo R, Mills-Koonce WR (2012). Evocative gene-parenting correlations and academic performance at first grade: an exploratory study. Dev Psychopathol 24:12654.
Pytliak M, Vargová V, Mechírová V, Felšöci M (2011). Serotonin receptors - from molecular biology to clinical applications. Physiol Res 60:15–25.
Ransohoff JD, Wei Y, Khavari PA (2018). The functions and unique features of long intergenic non-coding RNA. Nat Rev Mol Cell Biol 19:143–157.
Rapaport MH, Stein MB (1994). Serum interleukin-2 and soluble interleukin-2 receptor levels in generalized social phobia. Anxiety 1:50–53.
Raudales AM, Short NA, Schmidt NB (2020). Emotion dysregulation as a prospective predictor of suicidal ideation in an at-risk mixed clinical sample. Arch Suicide Res 24(Suppl 2):S310–S322.
Restrepo-Lozano JM, Pokhvisneva I, Wang Z, Patel S, Meaney MJ, Silveira PP, et al. (2022). Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children. Mol Psychiatry 27:2742–2750.
Rietschel M, Beckmann L, Strohmaier J, Georgi A, Karpushova A, Schirmbeck F, et al. (2008). G72 and its association with major depression and neuroticism in large population-based groups from Germany. Am J Psychiatry 165:753–762.
van Rijn S, Swaab H (2020). Emotion regulation in adults with Klinefelter syndrome (47,XXY): neurocognitive underpinnings and associations with mental health problem’. J Clin Psychol 76:228–238.
van Rijn S, Swaab H, Aleman A, Kahn RS (2006). X chromosomal effects on social cognitive processing and emotion regulation: a study with Klinefelter men (47,XXY). Schizophr Res 84:1942–203.
van Rijn S, de Sonneville L, Swaab H (2018). The nature of social cognitive deficits in children and adults with Klinefelter syndrome (47,XXY). Genes Brain Behav 17:e12465.
Rinieris PM, Christodoulou GN, Stefanis CN (1980). Neuroticism and ABO blood types. Acta Psychiatr Scand 61:473–476.
Rocklin T, Revelle W (1981). The measurement of extraversion: a comparison of the Eysenck Personality Inventory and the Eysenck Personality Questionnaire. Br J Soc Psychol 20:279–284.
Rodríguez-Ramos A, Moriana JA, García-Torres F, Ruiz-Rubio M (2019). Emotional stability is associated with the MAOA promoter uVNTR polymorphism in women. Brain Behav 9:e01376.
Roelofs RL, Wingbermühle E, Freriks K, Verhaak CM, Kessels RPC, Egger JIM (2015). Alexithymia, emotion perception, and social assertiveness in adult women with Noonan and Turner syndromes. Am J Med Genet A 167A:4.
Roelofs RL, Wingbermühle E, van der Heijden PT, Jonkers R, de Haan M, Kessels RPC, et al. (2020). Personality and psychopathology in adults with Noonan Syndrome. J Clin Psychol Med Settings 27:256–267.
Rogers J, Raveendran M, Fawcett GL, Fox AS, Shelton SE, Oler JA, et al. (2013). CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression. Mol Psychiatry 18:700–707.
Romanowska J, Joshi A (2019). From genotype to phenotype: through chromatin. Genes 10:76E76.
Sacchinelli E, Piras F, Orfei MD, Banaj N, Salani F, Ciaramella A, et al. (2018). IL-18 serum levels and variants of the serotonin transporter gene are related to awareness of emotions in healthy subjects: a preliminary study. Neuroimmunomodulation 25:129–137.
Salinas V, Villarroel J, Silva H, Herrera L, Jerez S, Zazueta A, et al. (2020). SERT and BDNF polymorphisms interplay on neuroticism in borderline personality disorder. BMC Res Notes 13:61.
Samochowiec J, Syrek S, Michał P, Ryzewska-Wódecka A, Samochowiec A, Horodnicki J, et al. (2004). Polymorphisms in the serotonin transporter and monoamine oxidase A genes and their relationship to personality traits measured by the Temperament and Character Inventory and NEO Five-Factor Inventory in healthy volunteers. Neuropsychobiology 50:174–181.
Schmitz A, Kirsch P, Reuter M, Alexander N, Kozyra E, Kuepper Y, et al. (2009). The 5-HT1A C(-1019)G polymorphism, personality and electrodermal reactivity in a reward/punishment paradigm. Int J Neuropsychopharmacol 12:383–392.
Schneider-Hassloff H, Straube B, Jansen A, Nuscheler B, Wemken G, Witt SH, et al. (2016). Oxytocin receptor polymorphism and childhood social experiences shape adult personality, brain structure and neural correlates of mentalizing. NeuroImage 134:671–684.
Schneider-Matyka D, Jurczak A, Samochowiec A, Karakiewicz B, Szkup M, Grzywacz A, et al. (2016). Analysis of personality traits and their influence on the quality of life of postmenopausal women with regard to genetic factors. Ann Gen Psychiatry 15:1.
Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A, et al. (2003). A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28:397–401.
Sen S, Villafuerte S, Nesse R, Stoltenberg SF, Hopcian J, Gleiberman L, et al. (2004). Serotonin transporter and GABAA alpha 6 receptor variants are associated with neuroticism. Biol Psychiatry 55:244–249.
Sheikh HI, Kryski KR, Smith HJ, Hayden EP, Singh SM (2013). Corticotropin-releasing hormone system polymorphisms are associated with children’s cortisol reactivity. Neuroscience 229:1–11.
Sher L, Greenberg BD, Murphy DL, Rosenthal NE, Sirota LA, Hamer DH (2000). Pleiotropy of the serotonin transporter gene for seasonality and neuroticism. Psychiatr Genet 10:125–130.
Shields A, Cicchetti D (1997). Emotion regulation among school-age children: the development and validation of a new criterion Q-sort scale. Dev Psychol 33:906–916.
Shifman S, Bhomra A, Smiley S, Wray NR, James MR, Martin NG, et al. (2008). A whole genome association study of neuroticism using DNA pooling. Mol Psychiatry 13:302–312.
Sifneos PE (1986). The Schalling-Sifneos personality scale revised. Psychother Psychosom 45:161–165.
Sirota LA, Greenberg BD, Murphy DL, Hamer DH (1999). Non-linear association between the serotonin transporter promoter polymorphism and neuroticism: a caution against using extreme samples to identify quantitative trait loci. Psychiatr Genet 9:35–38.
Skakkebæk A, Moore PJ, Pedersen AD, Bojesen A, Kristensen MK, Fedder J, et al. (2018). Anxiety and depression in Klinefelter syndrome: the impact of personality and social engagement. PLoS One 13:e0206932.
Smith DJ, Escott-Price V, Davies G, Bailey MES, Colodro-Conde L, Ward J, et al. (2016). Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci. Mol Psychiatry 21:749–757.
Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA, et al. (2002). Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet 114:230–234.
Strauss J, Barr CL, George CJ, King N, Shaikh S, Devlin B, et al. (2004). Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. Am J Med Genet B Neuropsychiatr Genet 131B:16–19.
Strohmaier J, Amelang M, Hothorn LA, Witt SH, Nieratschker V, Gerhard D, et al. (2013). The psychiatric vulnerability gene CACNA1C and its sex-specific relationship with personality traits, resilience factors and depressive symptoms in the general population. Mol Psychiatry 18:607–613.
Suchanecka A, Chmielowiec J, Chmielowiec K, Masiak J, Sipak-Szmigiel O, Sznabowicz M, et al. (2020). Dopamine receptor DRD2 gene rs1076560, personality traits and anxiety in the polysubstance use disorder. Brain Sci 10:E262.
Sundaram K, Mahajan S (1980). Theoretical studies on tricyclic antidepressants. I. Molecular structures. Physiol Chem Phys 12:323–336.
Swart M, Bruggeman R, Larøi F, Alizadeh BZ, Kema I, Kortekaas R, et al. (2011). COMT Val158Met polymorphism, verbalizing of emotion and activation of affective brain systems. NeuroImage 55:3381.
Tabak BA, Young KS, Torre JB, Way BM, Burklund LJ, Eisenberger NI, et al. (2020). Preliminary evidence that CD38 moderates the association of neuroticism on amygdala-subgenual cingulate connectivity. Front Neurosci 14:11.
Taylor GJ (1984). Alexithymia: concept, measurement, and implications for treatment. Am J Psychiatry 141:725–732.
Taylor GJ, Bagby RM, Parker JDA (2003). The 20-item Toronto alexithymia scale. IV. Reliability and factorial validity in different languages and cultures. J Psychosom Res 55:277–283.
Terock J, Van der Auwera S, Janowitz D, Homuth G, Hannemann A, Schmidt CO, et al. (2018). Childhood trauma and functional variants of 5-HTTLPR are independently associated with alexithymia in 5,283 subjects from the general population. Psychother Psychosom 87:581.
Terock J, Weihs A, Teumer A, Klinger-König J, Janowitz D, Grabe HJ (2021a). Associations and interactions of the serotonin receptor genes 5-HT1A, 5-HT2A, and childhood trauma with alexithymia in two independent general-population samples. Psychiatry Res 298:113783.
Terock J, Hannemann A, Weihs A, Janowitz D, Grabe HJ (2021b). Alexithymia is associated with reduced vitamin D levels, but not polymorphisms of the vitamin D binding-protein gene. Psychiatr Genet 31:4.
Terracciano A, Balaci L, Thayer J, Scally M, Kokinos S, Ferrucci L, et al. (2009). Variants of the serotonin transporter gene and NEO-PI-R neuroticism: no association in the BLSA and SardiNIA samples. Am J Med Genet B Neuropsychiatr Genet 150B:1070–1077.
Terracciano A, Sanna S, Uda M, Deiana B, Usala G, Busonero F, et al. (2010). Genome-wide association scan for five major dimensions of personality. Mol Psychiatry 15:647–656.
Thompson RA (2019). Emotion dysregulation: a theme in search of definition. Dev Psychopathol 31:805–815.
Tochigi M, Umekage T, Kato C, Marui T, Otowa T, Hibino H, et al. (2005). Serotonin 2A receptor gene polymorphism and personality traits: no evidence for significant association. Psychiatr Genet 15:67–69.
Tochigi M, Kato C, Otowa T, Hibino H, Marui T, Ohtani T, et al. (2006a). Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits. Psychiatry Clin Neurosci 60:524–526.
Tochigi M, Otowa T, Hibino H, Kato C, Otani T, Umekage T, et al. (2006b). Combined analysis of association between personality traits and three functional polymorphisms in the tyrosine hydroxylase, monoamine oxidase A, and catechol-O-methyltransferase genes. Neurosci Res 54:180–185.
Tsai S-J, Hong C-J, Yu YW, Chen T-J (2004). Association study of a brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and personality trait and intelligence in healthy young females. Neuropsychobiology 49:13–16.
Tu H, Kastin AJ, Pan W (2007). Corticotropin-releasing hormone receptor (CRHR)1 and CRHR2 are both trafficking and signaling receptors for urocortin. Mol Endocrinol 21:700–711.
Turley P, Walters RK, Maghzian O, Okbay A, Lee JJ, Fontana MA, et al.; 23andMe Research Team (2018). Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat Genet 50:229–237.
Umekage T, Tochigi M, Marui T, Kato C, Hibino H, Otani T, et al. (2003). Serotonin transporter-linked promoter region polymorphism and personality traits in a Japanese population. Neurosci Lett 337:13–16
Unschuld PG, Ising M, Specht M, Erhardt A, Ripke S, Heck A, et al. (2009). Polymorphisms in the GAD2 gene-region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 150B:1100–1109.
Urata T, Takahashi N, Hakamata Y, Iijima Y, Kuwahara N, Ozaki N, et al. (2007). Gene-gene interaction analysis of personality traits in a Japanese population using an electrochemical DNA array chip analysis. Neurosci Lett 414:209–212.
Vaht M, Laas K, Fernàndez-Castillo N, Kurrikoff T, Kanarik M, Faraone SV, et al. (2020). Variants of the aggression-related RBFOX1 gene in a population representative birth cohort study: aggressiveness, personality, and alcohol use disorder. Front Psychiatry 11:501847.
Venta A, Magyar M, Hossein S, Sharp C (2018). The psychometric properties of the personality assessment inventory-adolescent’s borderline features scale across two high-risk samples. Psychol Assess 30:827–833.
Verschoor E, Markus CR (2011). Affective and neuroendocrine stress reactivity to an academic examination: influence of the 5-HTTLPR genotype and trait neuroticism. Biol Psychol 87:439–449.
Viddal KR, Berg-Nielsen TS, Belsky J, Wichstrøm L (2017). Change in attachment predicts change in emotion regulation particularly among 5-HTTLPR short-allele homozygotes. Dev Psychol 53:7.
Vinberg M, Mellerup E, Andersen PK, Bennike B, Kessing LV (2010). Variations in 5-HTTLPR: relation to familiar risk of affective disorder, life events, neuroticism and cortisol. Prog Neuropsychopharmacol Biol Psychiatry 34:86–91.
Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA (2017). 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet 101:5–22.
Voigt G, Montag C, Markett S, Reuter M (2015). On the genetics of loss aversion: an interaction effect of BDNF Val66Met and DRD2/ANKK1 Taq1a. Behav Neurosci 129:801–811.
de Vroege L, Emons WHM, Sijtsma K, van der Feltz-Cornelis CM (2018). Psychometric properties of the Bermond–Vorst Alexithymia Questionnaire (BVAQ) in the general population and a clinical population. Front Psychiatry 9:111. https://www.frontiersin.org/article/10.3389/fpsyt.2018.00111. [Accessed 19 March 2022]
Wachleski C, Blaya C, Salum GA, Vargas V, Leistner-Segal S, Manfro GG (2008). Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder. Neurosci Lett 431:173–178.
Wacker J, Reuter M, Hennig J, Stemmler G (2005). Sexually dimorphic link between dopamine D2 receptor gene and neuroticism-anxiety. Neuroreport 16:611–614.
Waga C, Iwahashi K (2007). CYP2A6 gene polymorphism and personality traits for NEO-FFI on the smoking behavior of youths. Drug Chem Toxicol 30:343–349.
Wahlstrom LC, McChargue DE, Mackillop J (2012). DRD2/ANKK1 TaqI A genotype moderates the relationship between alexithymia and the relative value of alcohol among male college binge drinkers. Pharmacol Biochem Behav 102:3.
Walter NT, Montag C, Markett SA, Reuter M (2011). Interaction effect of functional variants of the BDNF and DRD2/ANKK1 gene is associated with alexithymia in healthy human subjects. Psychosom Med 73:23–28.
Wasserman D, Geijer T, Sokolowski M, Rozanov V, Wasserman J (2007). Genetic variation in the hypothalamic-pituitary-adrenocortical axis regulatory factor, T-box 19, and the angry/hostility personality trait. Genes Brain Behav 6:321–328.
Weiss EM, Freudenthaler HH, Fink A, Reiser EM, Niederstätter H, Nagl S, Parson W. (2014). Differential influence of 5-HTTLPR - polymorphism and COMT Val158Met - polymorphism on emotion perception and regulation in healthy women. J Int Neuropsychol Soc 20:5.
Westberg L, Melke J, Landén M, Nilsson S, Baghaei F, Rosmond R, et al. (2003). Association between a dinucleotide repeat polymorphism of the estrogen receptor alpha gene and personality traits in women. Mol Psychiatry 8:118–122.
Westberg L, Henningsson S, Landén M, Annerbrink K, Melke J, Nilsson S, et al. (2009). Influence of androgen receptor repeat polymorphisms on personality traits in men. J Psychiatry Neurosci 34:205–213.
Willis-Owen SAG, Fullerton J, Surtees PG, Wainwright NWJ, Miller S, Flint J (2005a). The Val66Met coding variant of the brain-derived neurotrophic factor (BDNF) gene does not contribute toward variation in the personality trait neuroticism. Biol Psychiatry 58:738–742.
Willis-Owen SAG, Turri MG, Munafò MR, Surtees PG, Wainwright NW, Brixey RD, Flint J (2005b). The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry 58:451–456.
Wingbermühle E, Egger JIM, Verhoeven WMA, van der Burgt I, Kessels RPC. (2012). Affective functioning and social cognition in Noonan syndrome. Psychol Med 42:2.
Wray NR, James MR, Mah SP, Nelson M, Andrews G, Sullivan PF, et al. (2007). Anxiety and comorbid measures associated with PLXNA2. Arch Gen Psychiatry 64:318–326.
Wray NR, James MR, Dumenil T, Handoko HY, Lind PA, Montgomery GW, Martin NG (2008a). Association study of candidate variants of COMT with neuroticism, anxiety and depression. Am J Med Genet B Neuropsychiatr Genet 147B:1314–1318.
Wray NR, James MR, Handoko HY, Dumenil T, Lind PA, Montgomery GW, et al. (2008b). Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression. Psychiatr Genet 18:219–225.
Wray NR, James MR, Gordon SD, Dumenil T, Ryan L, Coventry WL, et al. (2009). Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures. Biol Psychiatry 66:468–476.
Xu MK, Gaysina D, Tsonaka R, Morin AJS, Croudace TJ, Barnett JH, et al.; LHA Genetics Group (2017). Monoamine oxidase A (MAOA) gene and personality traits from late adolescence through early adulthood: a latent variable investigation. Front Psychol 8:1736.
Yang J, Mao Y, Niu Y, Wei D, Wang X, Qiu J (2020). Individual differences in neuroticism personality trait in emotion regulation. J Affect Disord 265:468–474.
Yen J-Y, Wang P-W, Su C-H, Liu T-L, Long C-Y, Ko C-H (2018). Estrogen levels, emotion regulation, and emotional symptoms of women with premenstrual dysphoric disorder: the moderating effect of estrogen receptor 1α polymorphism. Prog Neuropsychopharmacol Biol Psychiatry 82:216–223.
Zayats T, Yang B-Z, Xie P, Poling J, Farrer LA, Gelernter J (2013). A complex interplay between personality domains, marital status and a variant in CHRNA5 on the risks of cocaine, nicotine dependences and cocaine-induced paranoia. PLoS One 8:e49368.
Zhao S, Liu Z-G (2020). Integrative analysis of genome-wide association study and common meQTLs for exploring the effects of DNA methylation on the development of neuroticism. J Affect Disord 274:218–222.
Zimmerman M, Clark HL, Multach MD, Walsh E, Rosenstein LK, Gazarian D (2015). Have treatment studies of depression become even less generalizable? A review of the inclusion and exclusion criteria used in placebo-controlled antidepressant efficacy trials published during the past 20 years. Mayo Clin Proc 90:1180–1186.
Zou Z, Qiu J, Huang Y, Wang J, Min W, Zhou B (2019). The BDNF Val66Met gene polymorphism is associated with increased alexithymic and anticipatory anxiety in patients with panic disorder, Psychol Health Med 24:505–511.
Zuo L, Gelernter J, Kranzler HR, Stein MB, Zhang H, Wei F, et al. (2010). ADH1A variation predisposes to personality traits and substance dependence. Am J Med Genet B Neuropsychiatr Genet 153B:376–386.
Zupančič M, Kavčič T (2013). Neuroticism in early childhood: its measurement, development, and behavioral expressions. Psychol Neuroticism 1–42.

alexithymia; emotion dysregulation; genetic; genome-wide association study; neuroticism

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