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New insights and perspectives on the genetics of obsessive-compulsive disorder

Zai, Gwynetha,,b,,c; Barta, Csabad; Cath, Daniellee,,f; Eapen, Valsammag; Geller, Danielh; Grünblatt, Ednai,,j,,k

doi: 10.1097/YPG.0000000000000230
Review Articles

Psychiatric genetic research has exploded in search of polygenic risk factors over the past decade, but because of the complexity and heterogeneity of mental illnesses, using the current understanding of the genome has not reached the conclusion of finding a cause for psychiatric disorders. Obsessive-compulsive disorder is a relatively common and often debilitating neuropsychiatric disorder that has not been the primary focus in psychiatric research. Clinicians and researchers who have dedicated to investigate the genetics of obsessive-compulsive disorder have detected a strong genetic involvement. This review will provide an update and a new perspective on the current understanding of the genetics of obsessive-compulsive disorder, which includes epidemiological data, family and twins studies, candidate gene studies, genome-wide association studies, copy-number variants, imaging genetics, epigenetics, and gene–environment interaction.

aNeurogenetics Section, Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health

bDepartment of Psychiatry

cInstitute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

dInstitute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary

eGroningen University and University Medical Center Groningen, Department of Psychiatry, The Netherlands

fDrenthe Mental Health Institute, Department of Specialist Training, The Netherlands

gDepartment of Psychiatry, University of New South Wales, Sydney, Australia & Academic Unit of Child Psychiatry South West Sydney, Ingham Institute and Liverpool Hospital, Sydney, Australia

hMassachusetts General Hospital and Harvard University Medical School, Boston, MA, USA

iDepartment of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Switzerland

jNeuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland

kZurich Center for Integrative Human Physiology, University of Zurich, Switzerland

Received 30 April 2019 Accepted 18 June 2019

Correspondence to Gwyneth Zai, MD, Neurogenetics Section, Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5T 1R8, ON, Canada Tel: +1 416 535 8501; fax: +1 416 979 4666; e-mail:

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Obsessive-compulsive disorder (OCD) is a chronic and severe neuropsychiatric disorder, affecting 1–3% of the overall population (Ruscio et al., 2010). It has a lifetime prevalence of 2.3% and 12-month prevalence of 1.2% (Ruscio et al., 2010) in addition to subclinical rates for healthy individuals and individuals with other psychiatric disorders ranging from 13 to 17% and 31 to 49%, respectively (Fullana et al., 2009). OCD is characterized by chronic and often debilitating symptoms of obsessions and compulsions (American Psychiatric Association, 2013). Obsessions are irrational, unwanted, and intrusive thoughts, images, impulses, and urges that generate significant distress, whereas compulsions are repetitive rituals and mental acts that cannot be resisted and are performed in order to alleviate distress (American Psychiatric Association, 2013).

According to the WHO, OCD is one of the top 10 leading causes of disability globally and is the fourth most frequently diagnosed psychiatric disorder. Therefore, improving public awareness in addition to optimizing assessment and treatment is necessary to reduce the societal burden of OCD worldwide.

Treatment of OCD consists of two main streams, psychotherapy and pharmacotherapy. Cognitive behavior therapy (CBT) with exposure and response prevention is the first-line psychological treatment of OCD and serotonergic antidepressants are considered to be the first-line pharmacological treatment of OCD (Koran et al., 2007;Katzman et al., 2014). However, response rate varies ranging from 40 to 60% in medication treatment (McDougle et al., 1993;Foa et al., 2005) and 70 to 86% for CBT (Foa et al., 2005). Furthermore, both treatment options have limitations including side effects from the medications, commitment time, and access for CBT (Sadock et al., 2007). Currently, treatment guideline to differentiate patients according to their response and tolerability to medications and CBT does not exist. Thus, genetic profiling coupled with new knowledge on treatment outcome would provide a substantial leap in the management of OCD.

The underlying etiology of OCD remains largely unknown and improving the understanding of the biological mechanism of OCD will help guide research to optimize the identification of and treatment for this debilitating disease. Genetics has been studied extensively across psychiatric disorders and experts would agree that the underpinning of psychiatric disorders is at least partly due to polygenic effects.

Traditional genetic studies have utilized hypothesis-driven candidate gene approach. Specific genes were chosen based on the putative biological mechanisms and drug targets of existing psychotropic medications. With advances in genomic technology and bioinformatics, the use of genome-wide association studies (GWAS) has significantly increased in the past decade, which provided ways to investigate previously unexplored regions that may be of great importance in the etiology of OCD.

This review article will first provide an update on the heritability of OCD, followed by results from important human and animal candidate gene studies and GWAS (Burton et al., in press). Subsequently, this article will summarize studies on rare genetic variants, genetics of intermediate phenotypes including drug response and imaging, epigenetics in addition to gene–gene and gene–environment interactions (Burton et al., in press). Finally, this article will end with shared genetic phenomenon: overlap across psychiatric disorders, in light of the Brainstorm paper (Brainstorm et al., 2018), and future perspectives on the genetics of OCD.

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Heritability and familiality of obsessive-compulsive disorder

Family studies have shown that the prevalence of OCD in the relatives of individuals with OCD is higher than the general population, 10–12% versus 1–3%, respectively (Nestadt et al., 2000; Pauls, 2010; Pauls et al., 2014). Twin studies have estimated the heritability of OCD ranging from 42 to 65% (Pauls et al., 2014) for OCD symptoms, 27 to 47% for adult-onset OCD, and 45 to 65% for childhood-onset OCD (van Grootheest et al., 2005; Zilhao et al., 2019).

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Candidate gene studies in humans with obsessive-compulsive disorder

Evidence from genetic linkage and candidate gene studies has implicated the importance of several specific regions and genes in the pathoetiology of OCD. The following sections will highlight the major findings from human candidate gene studies of OCD.

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Serotonergic system genes

The serotonergic system is one of the most extensively studied systems in the genetics of OCD because of the rationale of using selective serotonin reuptake inhibitors (SSRIs) as the primary pharmacological treatment of OCD based on randomized clinical trials (CPA, 2006; Koran et al., 2007; Soomro et al., 2008; Davis et al., 2013; Murphy et al., 2013; Katzman et al., 2014; Bandelow et al., 2016). The widely known mechanism of action of SSRIs is that they increase the level of serotonin in the synaptic cleft in order to bind to postsynaptic receptors, which lead to the inhibition of its reuptake into the presynaptic cells. The target of SSRIs, the serotonin transporter coded by the SLC6A4 gene, has consistently been reported to be associated with OCD (Taylor, 2013; Brem et al., 2014; Walitza et al., 2014; Taylor, 2016). These studies have detected the LA allele of the single nucleotide polymorphism (SNP), rs25531, within the serotonin transporter-linked polymorphic region (5-HTTLPR) of this gene increases the risk for OCD. The serotonin 2A receptor (HTR2A) gene is another commonly studied candidate gene for OCD and based on the most recent meta-analysis (Taylor, 2013), it showed a nominally significant result for the rs6311 SNP [odds ratio (OR) = 1.219; 95% confidence interval (CI), 1.037–1.433; P = 0.003]. In addition to the most consistent findings for 5-HTTLPR and HTR2A rs6311 in OCD (Sinopoli et al., 2017), mixed results of other serotonergic genes with OCD, including monoamine oxidase A (MAOA), tryptophan hydroxylase (TPH1 and 2), and serotonin 1D-beta receptor (HTR1B), have been reported, which require further replication (Walitza et al., 2004; Liu et al., 2013; Taylor, 2013; Brem et al., 2014; Di Nocera et al., 2014; Mas et al., 2014; Sampaio et al., 2015).

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Glutamatergic system genes

Evidence has implicated the alteration of the glutamate system as part of the neuropathophysiological etiology of OCD, specifically with a disturbance in the cortico-striato-thalamo-cortical (CSTC) circuit (Pauls et al., 2014). Converging evidence from animal and human studies supports abnormal activation within this circuit, leading to hyperactivation of the orbitofrontal-subcortical pathway, which in turn mediates exaggerated concerns related to danger, harm, symmetry, and contamination, as seen in individuals suffering from OCD (Pauls et al., 2014). Additional rationale of the involvement of the glutamatergic system comes from magnetic resonance spectroscopy (MRS) studies, knock-out mouse models, and clinical trials of glutamatergic agents (Wu et al., 2012). The most studied glutamate gene is the neuronal glutamate transporter (SLC1A1) gene and although a general meta-analysis reported a nonsignificant association (Taylor, 2013), an in-depth meta-analysis by Stewart et al. (2013a) showed a moderately significant finding for SNPs across the 3′ region of the SLC1A1 gene including rs301443 (P = 0.046) and rs12682897 (P = 0.012) when controlled for gender. Dickel et al. (2006) also showed an association of rs378041 in SLC1A1 with early-onset OCD in males, which was replicated by Stewart et al. (2007a). Nonetheless, a recent study did not support a role of SLC1A1 in the risk of OCD (Kim et al., 2018) while others reported positive association in males [rs2228622 (Abdolhosseinzadeh et al., 2019); rs301443 (de Salles Andrade et al., 2019)]. Additional glutamate system genes that have been examined include: the glutamate receptor, ionotropic N-methyl D-aspartate (NMDA) 2B (GRIN2B) gene, which has also been reported to have a significant association with the diagnosis of OCD (Arnold et al., 2004); glutamate related synapse (SAPAP/DLGAP family); and NMDA receptor genes (GRIN and GRIK family) with mixed findings. Although no sex-specific SNP associations were reported, Khramtsova et al. (2018) found two significant gene-based associations in the glutamate ionotropic receptor delta type subunit 2 (GRID2) and G protein-coupled receptor 135 (GPR135) in females but no in males.

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Dopaminergic system genes

The dopaminergic system has been examined in OCD due to the effects of antipsychotics as adjunct medications to antidepressants for the treatment of OCD (Pauls et al., 2014). Additional studies using animal models, neuroimaging, and neurochemical approaches also implicate dopaminergic dysfunction in the pathophysiology of OCD (Koo et al., 2010). A meta-analysis (Taylor, 2013) showed a nominally significant finding for the catechol-O-methyltransferase (COMT) rs4680 marker (OR = 1.200, P = 0.010). COMT is involved in the turnover of monoamines in the brain. Five studies found that the low activity Met allele of the COMT rs4680 (Val158Met) SNP was overrepresented in males with OCD when compared with healthy males (Melo-Felippe et al., 2016). This was later confirmed to be disorder specific in males with OCD when comparing to other psychiatric disorders (Taylor, 2016). Inconsistent findings of the involvement of other dopaminergic system genes suggest that further investigations are warranted in significantly larger and well-characterized samples of OCD.

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Other genes

Several additional systems have been investigated in the genetics of OCD and they include the GABAergic system, neurotrophic system, and neuron-related genes. GABA-related genes have been studied with inconsistent and nonreplicated results (Taylor, 2013). Similar lack of support was reported for the brain-derived neurotrophic factor (BDNF) gene in OCD including the most studied Val66Met (rs6265) variant (Zai et al., 2015), in addition to genes related to neuroplasticity (Taylor, 2013). A recent study reported an overrepresentation of the BDNF rs6265 (Val-66-Met) Met allele in healthy individuals when compared with individuals with OCD and this allele was also significantly associated with lower contamination/washing symptom dimension score (Taj et al., 2018). Neuronal growth-related genes including the myelin-oligodendrocyte glycoprotein (MOG) (Zai et al., 2004) and oligodendrocyte lineage transcription factor 2 (OLIG2) (Stewart et al., 2007b; Zhang et al., 2015b) genes showed promising findings in OCD; however, these associations needs to be further confirmed and replicated.

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Candidate genes in obsessive-compulsive disorder identified through animal studies

Abnormalities within the CSTC circuitry, which involves the orbitofrontal cortex (OFC), anterior cingulate cortex, and striatum, have been consistently reported in OCD (Saxena and Rauch, 2000; Ting and Feng, 2011; Monteiro and Feng, 2016). Thus, novel animal models of OCD that can manipulate this circuit have been developed and used to further our understanding of the etiology of OCD. Four genetic animal models have been reported: SAP90/PSD95-associated protein 3 (SAPAP3) null mice, SLIT and NRTK-like family, member 5 gene (SLITRK5) null mice, homeobox B8 (HOXB8) null mice, and SLC1A1/EAAC1 null mice, in addition to a recent multispecies study in OCD.

SAPAP3 encodes a protein, which is highly expressed in the striatum. It is involved in postsynaptic scaffolding at excitatory (glutamatergic) synapses. Welch et al. (2007) showed that the SAPAP knock-out mice displayed abnormal behaviors consistent with an increase in anxiety and compulsive self-grooming, which were alleviated with repeated administration of fluoxetine. Three human genetic association studies later examined the role of this gene in OCD. Bienvenu et al. (2009) tested the association of SAPAP3 in 383 families with grooming disorders and reported nominally significant association with at least one grooming disorders but not with OCD alone. The second study sequenced SAPAP3 in patients with trichotillomania and OCD and detected significantly higher percentage of novel nonsynonymous heterozygous variants than healthy controls (4.2 versus 1.1%) (Züchner et al., 2009). The third study investigated seven variants within SAPAP3 in 172 patients with OCD, 45 patients with trichotillomania, and 153 healthy controls (Boardman et al., 2011) and observed a nominal association between rs11583978 and trichotillomania, which did not survive testing for multiple comparison. The authors also detected significant association between earlier age at onset of OCD and the A-T-A-T (rs11583978-rs7541937-rs6662980-rs4652867) haplotype when compared with the C-G-G-G haplotype, implicating this gene in the development of early onset OCD.

SLITRK5 encodes for a protein that regulates neurite outgrowth, which is important in neuronal survival. Shmelkov et al. (2010) reported that the SLITRK5 knock-out mice showed obsessive-compulsive-like behaviors including excessive self-grooming and increased anxiety in the open maze test, which were reversed using chronic fluoxetine treatment. SLITRK5 is widely expressed in the central nervous system and preferential increase in neuronal activity in the OFC of the SLITRK5 null mice was observed, which is consistent with human OCD functional imaging findings (Grünblatt et al., 2014).

HOXB8 encodes a nuclear protein that functions as a sequence-specific transcription factor, which has an important role in establishing body patterning during embryonic development. HOXB8 knockout mice were observed to develop compulsive self-grooming behavior and fur loss in addition to excessive grooming of wildtype (normal) caged-mice (Greer and Capecchi, 2002).

The fourth animal model has shown the greatest genetic contribution in OCD, which is consistent with human genetic findings. The neuronal excitatory amino acid carrier 1 (EAAC1), which is encoded by SLC1A1, plays a vital function in transporting glutamate and regulating postsynaptic action of glutamate; it is essential in maintaining extracellular glutamate concentrations below oxidative stress and toxic levels (Aoyama et al., 2006; Scimemi et al., 2009). Thirty percentage of EAAC1 null mice were found to have increased aggression in addition to excessive self-grooming and fur loss (Aoyama et al., 2006), which was reduced with N-acetyl-cysteine treatment, a prodrug of glutathione that modulates the glutamatergic system (Aoyama et al., 2006; Berman et al., 2011).

A recent investigation of 592 cases of OCD and 560 controls that sequenced 608 OCD candidate genes with their regulator elements (Noh et al., 2017) detected genome-wide significance for the neurexin 1α gene, NRXN1, which encodes the synapse cell-adhesion protein, neurexin 1α, a component of cortico-striatal neural pathway. This study demonstrated the genetic overlap with two animal models of compulsive behavior, in excessive grooming mice, and the so-called canine compulsive behavior. However, the five genes that these investigators found to be most associated with compulsive behavior in mice and dogs, including the well known SAPAP3 model, were significantly enriched for rare variants in the human sample, but did not reach statistical significance.

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Genome-wide association studies

There are four GWASs to date in OCD. The International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDFGC) conducted the first GWAS (Stewart et al., 2013b), which included 1465 patients with Caucasian OCD, 400 trios, and 5557 controls. For the trio subanalysis, an SNP near the BTB domain containing 3 gene (BTBD3) reached genome-wide significance (P = 3.84 × 10−8). For the case-control subanalysis, several intronic SNPs within the discs large homolog-associated protein 1 (DLGAP1), a gene previously found to be associated with OCD, also approached genome-wide significance. However, no genome-wide significant SNPs were identified in the combined trio and case-control analysis. This first GWAS identified top SNPs that were enriched for frontal lobe and methylation expression quantitative trait loci.

The OCD Collaborative Genetics Association Study consortium performed the second GWAS on a sample of 5061 individuals including 1065 families with 1406 patients with childhood-onset OCD, and unrelated population-based controls (Mattheisen et al., 2015). A marker mapped close to the protein tyrosine phosphatase, receptor type D gene (PTPRD) was found to approach genome-wide significance (P = 4.13 × 10–7), and loci near the cadherin genes, CDH9 and CDH10, were detected to have the next lowest P value (P = 1.76 × 10–6 and 1.13 × 10–5).

A recent meta-analysis of the first and second GWASs was published with a total sample of 2688 Caucasian patients with OCD and 7037 ancestry-matched controls (International Obsessive Compulsive Disorder Foundation Genetics and Studies, 2018). Although there was no genome-wide significant markers, the SNPs with the lowest P values tagged the haplotype blocks close to or within the cancer susceptibility 8 (CASC8/CASC11), glutamate ionotropic receptor delta type subunit 2 (GRID2), and KIT proto-oncogene receptor tyrosine kinase (KIT) genes. Previously detected markers in other GWASs have also been detected as top SNPs in this combined GWASs meta-analysis: Ankyrin repeat and SOCS box containing 13 (ASB13), GRIK2, CHD20, DLGAP1, fas apoptotic inhibitory molecule 2 (FAIM2), PTPRD, and R-spondin 4 (RSPO4). Gene enrichment analysis conducted from the results of the first two OCD GWASs yielded a molecular landscape that was enriched for proteins involved in synaptic plasticity via regulation of postsynaptic dendritic spine formation through insulin-dependent signalling cascades (van de Vondervoort et al., 2016).

The most recent GWAS analyzed 6931 participants with obsessive-compulsive symptoms (OCS) from The Netherlands Twin Registry (NTR), which identified a genome-wide significant marker (rs8100480) in the BLOC-1 related complex subunit 8 (BORCS8 or MEF2BNB) gene in addition to four significant hits within the myocyte enhancer factor 2B (MEF2B) family (den Braber et al., 2016). Polygenic risk score based on the IOCDFGC GWAS significantly predicted OCS, implicating that OCS may potentially be useful in gene discovery for OCD.

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Copy number variation in obsessive-compulsive disorder

Other genetic variations including copy number variations (CNVs) using cytogenetic technologies and rare genetic mutation using whole exome or whole genome sequencing techniques should be considered when investigating the underlying genetic risk of OCD.

Microsatellite repeat markers including SLC6A4 5-HTTLPR and STin2 VNTR, BDNF (GT)n, DAT1 VNTR, and DRD4 VNTR have previously been examined in the genetic basis of OCD. A meta-analysis comprising eight datasets examined the 5-HTTLPR marker and reported an overall significant result (mean OR = 1.251; 99th percentile CI, 1.048–1.492; P = 0.001) (Taylor, 2013). This meta-analysis only investigated biallelic SNPs and thus, multiallelic markers and haplotyptes for genetic association with OCD were not included.

To date, several studies have examined CNVs in OCD. Walitza et al. (2012) investigated the rs6311 marker in HTR2A in 136 pediatric individuals with OCD and a CNV within the HTR2A promoter region was significantly associated with the risk for OCD, its onset and severity (Taylor, 2016). A study conducted by the IOCDFGC group (McGrath et al., 2014) did not detect an increase in global CNV burden in OCD but the findings implicated a 3.3-fold increased burden of large deletions on chromosome 16p13.11, a region previously associated with other neurodevelopmental disorders. Another recent study observed a significantly higher frequency of rare CNVs, especially deletions, affecting brain-related genes, in individuals with OCD when compared with healthy controls (Grünblatt et al., 2017). Additional CNV variants that have been detected to date are mostly involved in immune processes and neuronal development (Delorme et al., 2010; Fernandez et al., 2012; Walitza et al., 2012; Nag et al., 2013; Cappi et al., 2014; McGrath et al., 2014; Gazzellone et al., 2016).

A whole exome sequencing study (Cappi et al., 2014) of 20 OCD cases and their unaffected parents detected an increase in de-novo mutation rate relative to the healthy controls from the publicly available 1000 Genomes Project. The mutations identified in the OCD individuals suggested an enrichment of genes involved in immunological systems and the central nervous system.

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Pharmacogenetics of antidepressants in obsessive-compulsive disorder

Pharmacogenetics has become increasingly important in the pharmacological treatment of psychiatric disorders because only approximately 50% of patients respond to psychotropic medications in general. Interindividual genetic variations have been the focus of the identification of predictors of drug response and tolerability.

Previous pharmacogenomics studies in OCD reported trends in known genetic variations across the cytochrome P450 liver enzymes, glutamatergic, and serotonergic system genes (Zai et al., 2014).

CYP450 is extensively involved in drug metabolism that plays a central role in medicine. Many medications are not only substrates for these enzymes but may also inhibit or induce enzymatic activity. Genetic variations encoding CYP450 enzymes can lead to alteration of metabolism, which can influence clinical response and adverse events of medications (Elliott et al., 2017). There are many genes coding for CYP450 enzymes that metabolize SSRIs, but only CYP2D6 and CYP2C19 have been studied using small sample sizes (Van Nieuwerburgh et al., 2009; Müller et al., 2012; Brandl et al., 2014). Brandl et al. (2014) has reported that individuals with CYP2D6 nonextensive metabolism (intermediate, poor, and ultrarapid metabolisms) were found to be associated with higher number of antidepressant trials (48 versus 22% with ≥4 trials; P = 0.007) and greater side effects from venlafaxine (P = 0.022).

Psychotropic medications have pharmacodynamic mechanism of actions, interacting with various neurotransmitter systems including sertonergic, glutamatergic, and dopaminergic systems, which have all been implicated in antidepressant treatment response and adverse effects in OCD (Zai et al., 2014). Serotonergic genes that have been previously examined in OCD include: SLC6A4 and its promoter (5-HTTLPR), HTR2A, HTR2C, HTR1B, and TPH. However, only one study (Corregiari et al., 2012) reported a significant finding between HTR2A rs6305 and nonresponders. Real et al. (2010) and Zhang et al. (2015a) examined the glutamatergic gene SLC1A1 to prospective SSRI response and reported a significant association with rs301434 and SSRI nonresponse, and between rs301430 and fluoxetine response. A recent study detected significant associations between SLC1A1 rs2228622 and rs3780413 with fluvoxamine response (Abdolhosseinzadeh et al., 2019). Five studies, investigating the dopaminergic DRD2, DRD4, COMT, and MAOA, have been performed, but they were all negative (Zhang et al., 2004; Miguita et al., 2011; Vulink et al., 2012; Viswanath et al., 2013; Umehara et al., 2015) except for COMT rs4680 Met/Met genotype with citalopram response (Vulink et al., 2012). Several studies conducted in other candidate genes have detected inconsistent results (Zai et al., 2014). The first pharmacogenetic GWAS of OCD (Qin et al., 2016) was conducted in 804 OCD cases and detected one significant finding with antidepressant response and the DISP1 rs17162912 SNP (P = 1.76 × 10–8); however, this finding was not replicated in an independent OCD sample (Lisoway et al., 2018). Further research is required to clarify the potential roles of these genes in OCD pharmacogenetics.

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Endophenotype genetics

The use of endophenotypes as a way to ascertain homogeneous phenotypes for genetic studies has provided important avenue to elucidate the etiology of OCD. The search of endophenotypes in the genetics of OCD has been generally guided by their strong association with OCD, high heritability, and observable similar deficits in unaffected relatives (Gottesman and Gould, 2003; Glahn et al., 2014). Endophenotypes may be of clinical utility in the search for underlying genetic diatheses and thus, for informing diagnostic classification and ultimately providing guidance to treatment management of OCD.

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Genetics of cognitive deficits in obsessive-compulsive disorder

Deficits across several cognitive domains with inconsistency have been reported in individuals with OCD. The observed cognitive deficits in OCD are mainly within the executive function domain (Tükel et al., 2012), cognitive inflexibility (Chamberlain et al., 2006; Bradbury et al., 2011) and motor inhibitory control deficits (Chamberlain et al., 2005). Only three genetic studies to date have examined the effects of genetic vulnerability to these cognitive deficits in OCD (da Rocha et al., 2011; Tükel et al., 2012, 2013). The studies examined a functional genetic variation within BDNF and COMT in cognitive functions of individuals with OCD. The authors observed poorer performance of the Trail-Making Test (TMT) in OCD COMT rs4680 Met carrier, suggesting that the lower activity enzyme with higher level of dopamine in the prefrontal cortex may lead to poorer executive function in patients with OCD (Tükel et al., 2013). Tükel et al. (2012) also reported that the BDNF rs6265 Met carriers had significantly slower performance on TMT A and B and poorer performance on verbal fluency when compared with healthy control Met carriers (Tükel et al., 2012). The other study showed the BDNF rs6265 Met carriers exhibited lower performance on decision making under ambiguous conditions only (da Rocha et al., 2011) but no significant differences in the TMT task performance. Replication studies with larger samples and the development of a broad cognitive battery with systematic and well standardized cognitive tasks that are reliable, easy to interpret, and comparable based on modern cognitive neuroscience approaches will be required in order to derive more definitive conclusions.

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Imaging genetics of obsessive-compulsive disorder

Imaging genetics utilizes neuroimaging and genetics to assess the impact of genetic variations on brain function and structure. Recently, large international efforts have begun to use imaging genetics approach on large sample sizes (i.e., ENIGMA, IMAGEN, ADNI, CHARGE) (Medland et al., 2014; Thompson et al., 2014; Bearden and Thompson, 2017; Bogdan et al., 2017). Imaging genetics studies in OCD to date have mainly focused on candidate genes (Arnold et al., 2009a,b; Scherk et al., 2009; Atmaca et al., 2010, 2011; Hesse et al., 2011; Wu et al., 2013; Wolf et al., 2014; Gassó et al., 2015; Mas et al., 2016; Ortiz et al., 2016; Honda et al., 2017). A systematic review (Grünblatt et al., 2014) reported that the main genetic pathways investigated in OCD were among the commonly studied neurotransmitter systems, the serotonergic, glutamatergic, and dopaminergic systems. Within the serotonergic system, the OFC and the raphe nuclei have been found to be associated with the SLC6A4 5-HTTLPR gene variant (Grünblatt et al., 2014). A recent study observed a reduction of gray matter volumes in the right frontal pole in OCD LA allele carriers when compared with healthy controls (Honda et al., 2017). With regard to the glutamatergic system, the CSTC circuit, OFC, thalamus, and anterior cingulate cortex (ACC) have been detected to be associated with several gene variations in glutamate-related genes (Honda et al., 2017). The increased concentrations of choline measured by 1H-MRS in the ACC of individuals with OCD have been associated with SNPs in the glutamate receptor AMPA1 gene (GRIA1) (Ortiz et al., 2016). Mean diffusivity in the right anterior and posterior cerebellar lobes has been observed to be associated with the SLC1A1 rs3087879 marker in patients with OCD (Gassó et al., 2015). Several studies on dopaminergic loci and imaging data have reported a positive association between the dopamine transporter gene (SLC6A3) and the metabolism of N-acetylaspartate in the putamen as measured by MRS (Grünblatt et al., 2014), in addition to the mean diffusivity of the white matter in right anterior and posterior cerebellar lobes (Gassó et al., 2015).

Given the complexity and heterogeneity of OCD phenotype, current efforts have been focused on combining polygenic risk scores with neuroimaging, particularly in large consortia, in order to overcome ongoing low statistical power in imaging genetic studies, such as in the ENIGMA consortium (Bearden and Thompson, 2017). Additional techniques including novel biostatistical approaches (Bearden and Thompson, 2017; Bogdan et al., 2017; Mattingsdal et al., 2013: Meda et al., 2012; Nymberg et al., 2013) and machine learning (Mas et al., 2016) have been developed for the prediction of diagnosis, prognosis, and treatment response.

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Epigenetics of obsessive-compulsive disorder

Epigenetics refers to the heritable changes in gene expression via DNA methylation or histone modification without changes to the underlying DNA sequence – a change in phenotype without a change in genotype.

In a genome-wide DNA methylation analysis of blood cells from 65 OCD patients and 96 healthy controls, several differentially methylated genes have been identified, which include previously implicated candidate genes for OCD such as BCYRN1, BCOR, FGF13, HLA-DRB1, ARX, etc. These results further suggest the important role of epigenetic phenomena in the development of OCD (Yue et al., 2016). However, these same findings were not replicated in a smaller study that analyzed 14 candidate genes including SLC1A1, SLC25A12, GABBR1, GAD1, DLGAP1, MOG, BDNF, OLIG2, NTRK2, NTRK3, ESR1, SLC6A4, TPH2, and COMT (Nissen et al., 2016). Another study observed an increase in the methylation level at the oxytocin receptor (OXTR) gene in patients with OCD than in healthy controls and the level of methylation was found to be correlated with OCD symptom severity (Cappi et al., 2016). Grünblatt et al. (2018) reported a significantly higher SLC6A4 DNA methylation levels in pediatric OCD patients when compared with controls and adults with OCD. Cappi et al. (2016) observed that individuals with OCD showed more DNA methylation than healthy controls in exons of the oxytocin receptor gene (OXTR) using peripheral blood leukocytes.

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Gene x gene and gene x environment interactions

The first family study examining gene–gene interaction is the Brazilian collaborative group and they investigated the epistatic effect between COMT and MAOA in 783 OCD trios (Sampaio et al., 2015), which was negative. Significant gene–gene interactions have been detected between COMT rs362204 and two SNPs across the monoamine oxidase B (MAO-B) gene, rs1799836 and rs6651806 (McGregor et al., 2016).

Heritability estimates of OCD have detected the importance of specific environmental factors that interact closely with genetic vulnerability, which in turn increase the risk of developing OCD. A population-based study of environmental risk factors for OCD (Brander et al., 2016a) found that impaired fetal growth, preterm birth, breech presentation, Cesarean section, and maternal smoking during pregnancy were associated with the susceptibility of developing OCD (Brander et al., 2016b, 2017). This study also identified a dose-response relationship between the environmental exposures and the development of OCD. The risk modifier for OCD, group A streptococcal infections, have not been consistently demonstrated to date (Hoekstra et al., 2013; Brander et al., 2016a). A recent systematic review has postulated that environmental factors may only increase the OCD risk in genetically susceptible individuals (Brander et al., 2016a).

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Shared genetic basis with other psychiatric disorders

Multiple cross-disorder genetic studies have revealed both shared and distinct genetic basis between OCD and several other psychiatric disorders including anorexia nervosa (Yilmaz et al., 2018), autistic spectrum disorder (Guo et al., 2017), attention deficit hyperactivity disorder (Ritter et al., 2017), Tourette disorder (Davis et al., 2013; McGrath et al., 2014; Yu et al., 2015; Zilhão et al., 2016), and schizophrenia (Costas et al., 2016), suggesting common biological mechanism across psychiatric disorders and common genetic markers causing different psychiatric disorders in general. A recent study by the Brainstorm Consortium conducted a collaborative GWAS meta-analysis for 25 brain disorders including psychiatric and neurological disorders in 265 218 cases and 784 632 controls and once again demonstrated significant genetic overlap between several different psychiatric disorders including the first group with anorexia nervosa, OCD, and schizophrenia, and the second group with Tourette disorder, OCD, and major depressive disorder (Brainstorm et al., 2018). These cross-disorder studies support an underlying shared genetic mechanism across various psychiatric disorders including OCD.

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Conclusion and future perspective

OCD is a psychiatric syndrome with diverse and heterogeneous symptom characteristics, complex genetics, and neurobiological mechanisms. Individuals with OCD often present with varied symptoms but treatment tends to be the same, either with the use of an SRI antidepressant, cognitive behavioral therapy, or a combination of both. Management of OCD has not provided tremendous success given its chronic, persisting, and heterogeneous nature. Therefore, improvement in precision medicine may enable clinicians to treat each patient with targeted therapies in the future.

Existing genomic studies have yielded important datasets and interesting findings that will require further exploration, in larger and well-characterized OCD samples. Because of the etiological, neurobiological, and therapeutic heterogeneity and complexity of OCD, it is not surprising that the identification of specific genetic factors has been relatively unproductive thus far. Most robust findings have implicated impairment of the cortico-striatal function and the glutamatergic neurotransmitter system, which have led to preliminary data, supporting the use of glutamatergic agents such as riluzole, memantine, N-acetylcysteine, in the treatment of OCD (Hirschtritt et al., 2017). However, it has been difficult to infer or identify from these results a precise pathophysiological mechanism for OCD or obvious molecular targets for novel treatments. The cause of OCD is likely a combination of common, rare inherited, and de-novo risk variants, suggesting a polygenic model of liability (Browne et al., 2014), in addition to nongenetic factors. Elucidating the genetic underpinnings of this condition has therefore been a major challenge due to the complexity of multifactorial involvements, and will require the integration of genomic, epigenomic, and gene-by-environment information.

In the next several decades, the field of psychiatric genomics will likely expand to involve international collaborative efforts, to use new developments in genetic knowledge (i.e., regulatory elements) and new advances in genetic technology (i.e., high-throughput genomics and biostatistical models), in combination with transcriptomics and proteinomics, to gain fresh new insight into the complex genetic architecture of OCD. Understanding the underlying biological mechanisms of OCD will hopefully lead to the introduction of new treatment strategies for this incapacitating psychiatric disorder. New discoveries certainly have the potential to transform the field of psychiatric genetics, which is moving along the goal of eventual translation into clinical practice. These new advances promise new understanding and novel avenues for prevention and treatment of mental illnesses; but they will also present with significant clinical and ethical challenges.

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I would like to acknowledge the members of the International Obsessive-Compulsive Disorder Foundation (IOCDF) Genetics Collaborative (IOCDFGC), especially Dr. Christie L. Burton and Dr. Odile A. van den Heuvel for their contribution on this review article.

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Conflicts of interest

There are no conflicts of interest.

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      epigenetics; genetics; gene–environment interaction; gene–gene interaction; imaging genetics; obsessive-compulsive disorder; pharmacogenetics

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