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Genetic aspects of early menopause

Fu, Xiaoyia; Wang, Hongyanb; Zhang, Xiaojinb,*

doi: 10.1097/JBR.0000000000000043
Review Articles
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Menopause is a biological event associated with the complete cessation of a woman's reproductive ability. Early menopause is defined as entry into menopause between the ages of 40 and 45 years, and has a significant impact on the fertility of affected women. Early menopause is a complex and heterogeneous disorder that is influenced by multiple genetic and environmental factors, as well as the interactions between these factors. Genome-wide association study (GWAS) is a novel strategy that has recently come into use as a way to overcome the limitations of genome-wide linkage analyses and candidate gene association approaches to discover novel susceptibility loci for early menopause. GWAS has identified many new candidate genes or loci associated with early menopause. In this review, we provide an overview of the current understanding of the genetic factors associated with early menopause that have been identified by GWAS. We also discuss potential approaches that could be used in the future to identify new genes associated with early menopause.

aState Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University

bObstetrics and Gynecology Hospital, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, China

Corresponding author: Xiaojin Zhang, Obstetrics and Gynecology Hospital, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China. E-mail: zxjgcp@126.com.

Received 6 March, 2019

Accepted 21 August, 2019

Online date: September 12, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

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Introduction

Menopause is a biological event associated with the complete cessation of a woman's reproductive ability. While the majority of women experience menopause between the ages of 45 and 55 years (with an average age of 51.4 years), approximately 5% of women enter menopause early, between the ages of 40 and 45 years. In addition, approximately 1% of women undergo premature menopause, also known as premature ovarian failure (POF) or premature ovarian insufficiency (POI), before the age of 40 years.[1–3] Early menopause or premature menopause is marked by amenorrhea, increased gonadotrophin levels, and estrogen deficiency, and can be induced or spontaneous. Induced early menopause or premature menopause can be the result of medical interventions, such as chemotherapy for cancer or surgery, such as bilateral oophorectomy. Although spontaneous early menopause or premature menopause can result from a wide spectrum of causes, such as autoimmune disorders, infections or inflammatory conditions, enzyme deficiencies, or metabolic syndromes,[4] genetic abnormalities or mutations have also been shown to play a significant role in early menopause or premature menopause. While several recent studies have used GWAS to identify novel genetic loci associated with the onset of menopause, few reviews have summarized these newly found genetic markers and their potential molecular mechanisms. Recent advances in our understanding of the genetic basis of POI have been extensively reviewed by Qin et al[1] and Jiao et al.[5] Therefore, this review will focus primarily on providing an introduction to early menopause and discussing recent evidence for the genetic basis of early menopause based on GWAS.

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Search strategy

The following strategies were used to search for candidate genes associated with early menopause. First, the PubMed database was searched from inception to 2018 for genetic studies of early menopause, using “early menopause” and/or “natural menopause” as the key words. Only studies of humans or mice were included. Studies including subjects from different ethnicities were included. Then, the reference lists of the included studies were scanned to identify other potentially useful studies. Only single nucleotide polymorphisms (SNPs) or genes that were identified more than once among these studies were extracted and summarized in this review.

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Menopause

Natural menopause is the time in a woman's life when her menstrual periods stop permanently, marking a cessation in her ability to bear children.[6] Menopause is considered to be complete when a woman has not had any vaginal bleeding for a year, in the absence of hormonal manipulation. The eventual cessation of menstrual periods is attributed to the loss of ovarian follicles. Women are born with one million primordial follicles and begin menarche with about 500,000; by the age of 40, perhaps only a few thousand remain.[7] It is logical to expect that, the fewer oocytes a woman has and the faster they are depleted, the sooner she will experience menopause. During a normal menstrual cycle, the ovaries produce, testosterone, and progesterone in a cyclical pattern under the control of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are both produced by the pituitary gland. Depletion of the ovarian reserve results in a decrease in E2 and progesterone levels, but an increase in circulating FSH and LH levels in the circulation. Clinically, a FSH level of 10 mIU/mL is considered the cutoff value between normal and diminished ovarian reserve.[8] During the perimenopausal period (a few years before and after menopause), women often experience multiple symptoms, including hot flashes, vasomotor symptoms, tachycardia, vaginal dryness, trouble sleeping, and night sweats. Some women also experience many psychological symptoms, such as anxiety, irritability, depressive mood, poor memory, and decreased interest in sexual activity.[9,10] The long-term effects of menopause include an increased risk of osteoporosis,[11] cardiovascular disease,[12] atherosclerosis,[13] and mortality.[14]

The timing of natural menopause onset varies substantially between individuals and different ethnic groups. In western countries, menopause normally occurs between the ages of 45 and 55, with an average age of approximately 51.4 years at onset.[15,16] However, the menopausal age ranges from as early as 40 to as late as 62.[6] In rare cases, a woman's ovaries stop working at a very early age, ranging anywhere from puberty to age 40.

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Early menopause and premature menopause

Menopause that occurs between the ages of 40 and 45 years is referred to as early menopause, and affects approximately 5% to 10% of women, while premature menopause, which occurs before the age of 40, occurs in approximately 1% to 2% of women.[17] Premature menopause was also known historically as POF, but this term was replaced with the term POI by the European Society of Human Reproduction and Embryology (ESHRE) in 2016.[18]

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Signs and symptoms

In addition to the signs and symptoms that occur with natural menopause, early entry into menopause causes severe anxiety in many women. Furthermore, the effect on fertility is one of the greatest impacts of early menopause. Early menopause is one of the principal causes of infertility in western countries.[19] Fertility normally starts to decrease at around 30 years of age and then begins to decline dramatically at the age of 41 years, with natural menopause normally occurring at around age 51. In women who experience early menopause, fertility begins to decline even earlier, resulting in a greatly shortened reproductive period. Women with a high risk of early menopause who have not given birth by the age of 30 will find it hard to conceive. Furthermore, early menopause increases the risk of developing cardiovascular disease and osteoporosis.[11]

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Diagnosis of early menopause

There are detailed diagnostic criteria for premature menopause or POI: (a) oligo/amenorrhea for at least 4 months, and (b) an elevated FSH level >25IU/L on two occasions 4 weeks apart.[18] However, there are no specified clinical diagnostic criteria for early menopause. The diagnosis of early menopause is mainly based on the presence of menstrual disturbance, clinical symptoms, and biochemical confirmation, in addition to a comprehensive clinical evaluation including gynecological and obstetrical history, details of previous uterine surgery, presence of symptoms of menopause, family history of early menopause and infertility, and the presence of autoimmune disease.[10] Measuring FSH, LH, and E2 levels is recommended to confirm the diagnosis in women suspected of experiencing early menopause. For example, FSH levels higher than 30 to 40IU/L are considered to be in the menopausal range. However, owing to natural variations in FSH levels in different individuals, diagnostic thresholds are difficult to define, making the test an unreliable indicator of menopause. Therefore, assessment of FSH levels should be paired with tests assessing other sex hormone levels.[20] For example, an E2 level of less than 50pg/mL indicates hypoestrogenism.[10]

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Causes of early menopause

Similar to premature menopause or POI, the cause of early menopause is usually idiopathic. Prophylactic bilateral oophorectomy before age 45 results in the abrupt onset of menopause, while 15% to 50% of women who have undergone hysterectomy experience ovarian failure later in life.[21] Some cases of early menopause can be attributed to autoimmune disorders, Turner syndrome, fragile X syndrome,[10,18,22] chemotherapy, or radiation.[23] Lifestyle choices and habits like cigarette smoking, excessive consumption of alcohol, or caffeine use are also associated with early entry into menopause.[24] However, these non-genetic factors explain only a small proportion of early menopause. Genetic factors contribute significantly to the age at onset of natural menopause. According to twin and family studies, the age at which natural menopause begins is highly heritable, with heritability scores of 44% to 65%.[25,26] A recent study showed that a woman whose mother experienced early menopause has a 6-fold higher risk of experiencing early menopause than a woman whose mother did not.[27]

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Genetic aspects of early menopause

Despite the strong genetic component, only a limited number of genes associated with early menopause have been identified, using the following three methods: genome-wide linkage analysis, candidate gene association, and GWAS.

Genome-wide linkage analysis requires family data and can detect rare variants with large genetic effects on diseases or traits, but is not suitable for the identification of variants with smaller effects. Due to the lack of large pedigrees, this method cannot be widely used to identify causative genes for early menopause. Nevertheless, genome-wide linkage analysis of the age at onset of natural menopause has indicated the involvement of one strong candidate locus, Xp21.3 (logarithm (base 10) of odds (LOD) = 3.1), and a few suggested loci at 9p21.3 (LOD = 2.6),[26] 8p22 (LOD = 2.6), 16p13.3 (LOD = 2.4), and 11q23.3 (LOD = 2.1).[25] However, these results have not been replicated, and remain to be further verified.

The candidate gene association approach is the primary method used to investigate the molecular basis of early menopause. Candidate causative genes are selected based on educated guesses of the associated pathways, for example, the estrogen pathway and pathways with molecular defects known to cause genetic diseases such as POI. MCM8 and MCM9, which are mutated in a few POF pedigrees,[28–30] are potential causative genes for early menopause. However, the candidate gene association approach is limited by incomplete knowledge of the human genome, and as such is likely to overlook important and novel genes or pathways. This is expected to be remedied in the future as more whole genomes are sequenced and made available in appropriate databases.

GWAS is a novel strategy that has been used recently to overcome the limitations of genome-wide linkage analysis and the candidate gene association approach in discovering novel susceptibility loci for early menopause. In the rest of this review, we have summarized the candidate genes that have been identified by GWAS as having a potential link to early menopause.

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Candidate genes in associated pathways that are closely related to menopause

An alternative approach to identifying causative genes for early menopause involves searching for alterations in genes involved in pathways that are closely related to menopause. A summary of SNPs and genes associated with age at the onset of natural menopause, with their associated pathways, is presented in Table 1.

Table 1

Table 1

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Candidate genes in sex steroid hormone metabolism and biosynthesis pathways

Early candidate gene studies primarily focused on genes involved in pathways associated with early menopause, including the sex steroid biosynthetic and metabolic pathways.

Estrogen receptor 1 (ESR1) is essential for sexual development and reproductive function, and thus represents a plausible candidate gene. ESR1 encodes estrogen receptor α, which regulates cyclic gonadotropin release at the hypothalamus-hypophysis-ovarian axis and may impact the age at which menopause begins. ESR1 was found to be associated with early menopause in different ethnic groups (including Dutch, Korean, and Chinese women) in some candidate gene studies,[31] although the association with ESR1 SNPs was less consistent in other populations.[32] One of the most frequently identified SNPs is rs2234693, which lies in an intronic region of ESR1 and is presumed to be in linkage disequilibrium with a regulatory sequence that may affect ESR1 expression or function, thereby resulting in changes in estrogen that impact the onset of menopause.

Cytochrome P450 1 subfamily B member 1 (CYP1B1) and cytochrome P450 19 subfamily A member 1 (CYP19A1), which encode two enzymes belonging to the CYP family, have been studied in association with the age at natural menopause onset. CYP1B1 catalyzes 4-hydroxylation, which is an important step in estrogen elimination. Women with a common polymorphism (rs1056836) in CYP1B1 experienced menopause 0.9 year earlier, had a 1.0-year shorter reproductive span, and had 12.6 fewer menstrual cycles than women without this allele, suggesting that CYP1B1 is associated with early menopause.[33]CYP19A1 contains several SNPs (rs10012, rs1056827, rs1056836, and rs1800440) that have previously been reported to be associated with the age at the onset of natural menopause.[34]

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Candidate genes involved in anti-Müllerian hormone signaling

Anti-Müllerian hormone (encoded by AMH) is a member of the transforming growth factor-β (TGFβ) family, and anti-Müllerian hormone receptor 2 (encoded by AMHR2) belongs to the family of type II receptors for TGFβ-related proteins. The primordial follicle pool is formed during fetal development. The recruitment of dormant primordial follicles into the growing follicle pool, a process referred to as initial recruitment, is inhibited by AMH/AMHR2 signaling in females.[35] The absence of AMH results in a prematurely exhausted follicle pool and, subsequently, an earlier cessation of the estrus cycle in AMH-deficient mice. However, association studies between AMH and AMHR2 SNPs and menopause in humans have yielded conflicting results. The AMH SNPs investigated showed no significant association with age at menopause, while a SNP in AMHR2 (rs2002555) was associated with an interaction between age at menopause and parity. Nulliparous women with a G/G genotype at this locus entered menopause 1.9 (P = 0.16) and 2.6 (P = 0.05) years earlier than nulliparous women with an A/A genotype at this locus. However, parous women with the G/G genotype experienced menopause 1 year later than those with the A/A genotype (P = 0.01).[35,36] Each copy of the rs11170547 minor allele (T) is associated with a 0.41-year delay in the onset of menopause in parous women. These findings suggest a potential role for AMH signaling in regulation of the primordial follicle pool in women, and therefore the role in the onset of menopause.[36]

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Candidate genes in the vascular pathway

SNPs in genes involved in the vascular pathway may interfere with ovarian function, and are associated with age at the onset of natural menopause.[37] Therefore, these genes are thought to be candidate genes for regulating the onset of menopause. However, results so far have been conflicting, and additional studies are needed.[16,38]

Nitric oxide synthase 3 (NOS3) encodes endothelial nitric oxide synthase, an enzyme that catalyzes production of the free radical nitric oxide by converting L-arginine to L-citrulline. NOS3 was previously reported to be involved in human reproductive processes such as pregnancy and ovulation. A Nos3-deficient mouse model exhibited reduced ovulation rates, fewer deliveries, and earlier onset of menopause compared with wild-type mice.[39] However, 2 studies reported that polymorphisms in NOS3 have no correlation with early menopause in humans, suggesting that NOS3 is not a good candidate gene for predicting early menopause.[40,41]

Factor V (encoded by F5) is a key component of the coagulation cascade in humans, and a common polymorphism in F5 (G1691A) is associated with early menopause in Dutch and middle European Caucasian women.[37,42] SNPs in APOE, which encodes apolipoprotein E, have been shown to be associated with dysfunctional vascular homeostasis, hypertension, atherosclerosis, and cardiovascular events in numerous studies. In middle European Caucasian women, a polymorphism in ApoE-2 (R158C) is positively correlated with premature early menopause.[37] It is possible that the increased susceptibility to venous thrombosis associated with polymorphisms in this gene interferes with the continuous availability of the ovarian follicle pool over the reproductive lifespan, and may therefore reduce the length of a woman's reproductive period.

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Candidate genes in pathways affecting development

As more GWASs focus on the age at natural menopause onset, biological pathway analysis has identified an enrichment of associated genes in pathways involved in processes like DNA repair, recombination, and replication, and the immune response.[43]

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Candidate genes in the DNA damage repair pathway

Recent studies have demonstrated that the accumulation of DNA damage is a major driver of aging.[44] The most plausible interpretation of the association between the DNA damage repair pathway and early menopause is that organs face accelerated aging due to rapid accumulation of DNA damage. Gradual accumulation of unrepaired DNA damage causes cell death and senescence, leading to exhaustion of the cell's renewal capacity and cellular dysfunction in affected organs and tissues like the ovary, and eventually aging throughout the entire body.

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BRCA1, FAM175A, and UIMC1

BRCA1 is a known tumor suppressor gene associated with breast and ovarian cancers. Mutations in this gene are responsible for approximately 40% to 65% of inherited breast cancers, and more than 80% of inherited breast and ovarian cancers.[45] It is involved in transcription and repair of double-strand DNA breaks via homologous recombination. The BRCA1 variant rs1799949 is associated with age at the onset of natural menopause.[46]

FAM175A binds directly to BRCA1 and functions as a central scaffold protein for assembly of the BRCA1-A complex, which is involved in the DNA damage response and double-strand break repair.[38,47]FAM175A is also thought to influence the age at natural menopause onset. Stolk et al[43] and Day et al[46] both showed that the rs4693089 variant of FAM175A associated with menopause onset, thus establishing a link between menopause and double-strand break repair.

Ubiquitin interaction motif containing 1 (UIMC1), another protein that interacts with BRCA1, is a ubiquitin-binding protein that binds ubiquitinated lysine 63 of histones H2A and H2AX.[48] This protein plays a central role in targeting the BRCA1-BARD1 heterodimer to double-strand DNA breaks.[49] GWAS studies have shown that two coding-synonymous SNPs (rs365132 and rs2241584) and an intronic SNP (rs7718874) in UIMC1 are all associated with age at the onset of natural menopause.[6,43]

Taken together, studies of these three genes demonstrate that there is an association between the DNA damage repair pathway and early menopause.

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MCM8 and MCM9

MCM8 and MCM9 are the most recently discovered members of the MCM family of proteins (MCM2–9), which all share a conserved helicase domain. Both MCM8 and MCM9 are mini-chromosome maintenance proteins and are also involved in homologous recombination-mediated DNA repair, the formation of replication forks, and the recruitment of other DNA replication-related proteins belonging to the DNA damage repair pathway.[50]

In mammals, both MCM8 and MCM9 are highly expressed in the testes and moderately expressed within the ovary, uterus, and vagina. Deletion of MCM8 in mice results in sterility (due to an early block of meiotic prophase I) and the development of ovarian tumors. Mice deficient in MCM9 are also sterile, and atrophied ovaries are typically observed in adult mice with this mutation.[51] In humans, pedigree studies and several GWAS studies have shown that these two genes have a fairly large effect on normal menopausal timing, with each minor allele increasing menopausal age by a single year.[43] Several SNPs in MCM8 (rs16991615, rs236114, rs16991615, and rs6139882) have been reported as candidate menopausal age modifiers in GWAS studies published from 2009 to 2014.[16,38,43]

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Candidate genes involved in cell cycle regulation

BRSK1

Brain serine/threonine kinase 1 (BRSK1) is highly expressed in the human brain and moderately expressed in mammalian ovaries. BRSK1 is involved in multiple functions in the brain, including neuronal polarization, centriole replication, and regulating neurotransmitter release at mature synapses with presynaptic cytomatrix.[52] Therefore, BRSK1 is hypothesized to affect the secretion of gonadotropin-releasing hormone from the hypothalamus-pituitary-ovarian axis, leading to early menopause.

In 2009, two GWAS studies identified common genetic variants influencing age at the onset of natural menopause in a pool of over 10,000 European women.[16,43] These two studies identified SNPs in four loci, 20p12.3 (in MCM8), 19q13.42 (in BRSK1), 5q32.2 (in/near UIMC1 and HK3), and 6p24 (in SYPC2L), and calculated that they explained 2.69% of the variations observed in age at the onset of natural menopause. In both studies, a common SNP, rs1172822, which is located in an intronic region in BRSK1, was significantly associated with age at natural menopause onset. In other ethnic populations, including Chinese and Caucasians,[53,54] rs1172822 and rs12611091 are strongly associated with early menopause, adding further support to the hypothesis that there is a relationship between BRSK1 and early menopause.

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HELB

HELB encodes a DNA helicase that catalyzes the unwinding of DNA, which is necessary for DNA replication, repair, recombination, and transcription. Although early mutational studies of human HELB suggested that HELB activity was critical for the G1/S cell cycle transition, recent studies have shown that HELB inhibits homologous recombination (HR) in the G1 phase by suppressing DNA end resection via its 5′–3′ translocase activity after being recruited to resected DSB ends through its interaction with RPA.[55,56] Nuclear export of HELB facilitates the activation of resection in the S phase in a CDK2-dependent manner.[55] Two HELB SNPs (rs3741604 and rs1183272) have been reported to be associated with age at menopause onset.[6,46]

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Other candidate genes and potential mechanisms

HK3

Hexokinase 3 (encoded by HK3) phosphorylates glucose to produce glucose-6-phosphate, which is the first step in most glucose metabolism pathways. HK3 is expressed in reproductive organs like the uterus and placenta, and is over-expressed in malignant follicular thyroid nodules.[57] Two HK3 SNPs (rs2278493 and rs691141) have been reported to be associated with early menopause, but there is no apparent functional explanation for this observation, which suggests that extensive pathway analysis and functional studies of HK3 gene variants are needed.

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TMEM150B

Transmembrane protein 150B (encoded by TMEM150B), also known as damage-regulated autophagy modulator (DRAM3), can repress cell death and promote the long-term clonogenic survival of cells grown in the absence of glucose. TMEM150B expression leads to the accumulation of autophagosomes under basal conditions and enhances autophagic flux, while TMEM150B deletion impairs autophagic flux, confirming that is a modulator of macroautophagy.[58,59] Several SNPs in TMEM150B, such as rs7246479, rs2384687, rs11668344, and rs897798, have been identified in different GWAS studies, and are strongly associated with early menopause.[16,43,60] With the exception of rs7246479, which is a missense variant, the other three SNPs are all in intronic regions and are predicted to have weak enhancer and repressor activities. BRSK1 and TMEM150B are both located on chromosome 19 on opposite strands, separated by only 268 base pairs. The presence of seven moderately correlated SNPs at the BRSK1/TMEM150B locus on chromosome 19 suggests that this genomic region is strongly associated with early menopause. Surprisingly, whole human genome studies have showed that SNPs or genes associated with menopause are enriched on chromosomes 13, 19, and 20.[38] Variants located on these chromosomes increase the chance of early menopause and suggest that genetic risk factors are important in determining early onset of menopause.[61]

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Perspective

Although a growing number of studies have focused on identifying genetic loci associated with early menopause, the loci that have been found can only explain a small proportion of the heritability of this condition. It is thus very likely that many relevant genetic loci remain to be identified. Applying new technologies/methods and combining them with previously used technologies/methods may help identify these unknown genetic factors associated with early menopause.

The GWAS chips used in most studies to date have focused on common genetic variants. Using whole genome sequencing, higher-density SNP chips, and exome chips will allow us to determine whether low frequency or rare variants with larger effects account for much of the heritability of early menopause.[62]

Expression quantitative trait loci (eQTL) analysis is a technique used to map genetic variants that influence gene expression levels. eQTL can establish links between significant SNPs identified by GWAS and genes whose expression levels are affected by the presence of these SNPs, and therefore provide support for the functional significance of candidate genes at an associated locus. Recent studies combining eQTL data and GWAS pathway analysis have shown that using these two approaches together is a powerful way to uncover important biological pathways and to advance our understanding of the biological mechanisms underlying a variety of diseases and traits.[63,64] Similarly, integrating GWAS results and eQTL analysis in relevant tissues such as the ovaries and the endometrium is expected to advance future GWAS analysis of the genetics of early menopause.[62]

The age of menopause onset is likely to be affected by multiple genes, each of which has only moderate effects. Thus, biological pathway-based analysis could also be used in combination with GWAS data to study the joint effects of multiple genes, taking a complementary approach to single-point analysis.

More importantly, the functions of the loci identified by GWAS and the molecular mechanisms underlying the effect on the age at menopause onset needs to be investigated. The loci identified by GWAS are primarily located in intronic regions, which make it challenging to determine their contributions to early menopause. Whole genome sequencing of noncoding RNAs or combined eQTL data and GWAS pathway analysis may help address this question. Animal models could also be used to determine whether the gene variants and loci identified in these studies affects fertility or ovarian function.

Currently, none of the single candidate genes identified by GWAS have been used clinically to predict the risk of early menopause. However, when more genes or loci associated with early menopause are identified in the future, it is plausible that these factors, alone or in combination with known environmental and/or lifestyle factors, will be able to be used clinically to predict early menopause.

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Acknowledgments

None.

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Author contributions

XF wrote the manuscript. HW and XZ revised the manuscript. All authors approved the final version of the manuscript.

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Financial support

This work was supported by the grants from the National Key Research and Development Program of China (No. 2016YFC1000500), the National Natural Science Foundation of China (No. 81430005, 31521003), and the Commission for Science and Technology of Shanghai Municipality (No. 13JC1407600); all to HW.

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Conflicts of interest

The authors declare that they have no conflict of interest.

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References

1. Qin Y, Jiao X, Simpson JL, et al. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update 2015; 21:787–808.
2. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med 2009; 360:606–614.
3. Panay N, Kalu E. Management of premature ovarian failure. Best Pract Res Clin Obstet Gynaecol 2009; 23:129–140.
4. Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas 2010; 65:161–166.
5. Jiao X, Ke H, Qin Y, et al. Molecular genetics of premature ovarian insufficiency. Trends Endocrinol Metab 2018; 29:795–807.
6. Laven JSE, Visser JA, Uitterlinden AG, et al. Menopause: genome stability as new paradigm. Maturitas 2016; 92:15–23.
7. Harlow BL, Signorello LB. Factors associated with early menopause. Maturitas 2000; 35:3–9.
8. Butler L, Santoro N. The reproductive endocrinology of the menopausal transition. Steroids 2011; 76:627–635.
9. Avis NE, Stellato R, Crawford S, et al. Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001; 52:345–356.
10. Luisi S, Orlandini C, Regini C, et al. Premature ovarian insufficiency: from pathogenesis to clinical management. J Endocrinol Invest 2015; 38:597–603.
11. Finkelstein JS, Brockwell SE, Mehta V, et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab 2008; 93:861–868.
12. Atsma F, Bartelink ML, Grobbee DE, et al. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006; 13:265–279.
13. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the Multi-Ethnic Study of Atherosclerosis. Menopause 2012; 19:1081–1087.
14. van der Schouw YT, van der Graaf Y, Steyerberg EW, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996; 347:714–718.
15. Hartge P. Genetics of reproductive lifespan. Nat Genet 2009; 41:637–638.
16. He C, Kraft P, Chen C, et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 2009; 41:724–728.
17. Faubion SS, Kuhle CL, Shuster LT, et al. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015; 18:483–491.
18. Webber L, Davies M, et al. European Society for Human Reproduction, Embryology (ESHRE) Guideline Group on POIESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod 2016; 31:926–937.
19. Perry JR, Corre T, Esko T, et al. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013; 22:1465–1472.
20. Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf) 2008; 68:499–509.
21. Okeke T, Anyaehie U, Ezenyeaku C. Premature menopause. Ann Med Health Sci Res 2013; 3:90–95.
22. Bachelot A, Rouxel A, Massin N, et al. Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure. Eur J Endocrinol 2009; 161:179–187.
23. Bedoschi G, Turan V, Oktay K. Utility of GnRH-agonists for fertility preservation in women with operable breast cancer: is it protective? Curr Breast Cancer Rep 2013; 5:302–308.
24. Kinney A, Kline J, Kelly A, et al. Smoking, alcohol and caffeine in relation to ovarian age during the reproductive years. Hum Reprod 2007; 22:1175–1185.
25. Murabito JM, Yang Q, Fox C, et al. Heritability of age at natural menopause in the Framingham Heart Study. J Clin Endocrinol Metab 2005; 90:3427–3430.
26. van Asselt KM, Kok HS, Pearson PL, et al. Heritability of menopausal age in mothers and daughters. Fertil Steril 2004; 82:1348–1351.
27. Morris DH, Jones ME, Schoemaker MJ, et al. Familial concordance for age at natural menopause: results from the Breakthrough Generations Study. Menopause 2011; 18:956–961.
28. AlAsiri S, Basit S, Wood-Trageser MA, et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest 2015; 125:258–262.
29. Wood-Trageser MA, Gurbuz F, Yatsenko SA, et al. MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet 2014; 95:754–762.
30. Bouali N, Francou B, Bouligand J, et al. New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family. Fertil Steril 2017; 108:694–702.
31. Yoon SH, Choi YM, Hong MA, et al. Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure. Hum Reprod 2010; 25:283–287.
32. Dvornyk V, Long JR, Liu PY, et al. Predictive factors for age at menopause in Caucasian females. Maturitas 2006; 54:19–26.
33. Long JR, Shu XO, Cai Q, et al. Polymorphisms of the CYP1B1 gene may be associated with the onset of natural menopause in Chinese women. Maturitas 2006; 55:238–246.
34. Mitchell ES, Farin FM, Stapleton PL, et al. Association of estrogen-related polymorphisms with age at menarche, age at final menstrual period, and stages of the menopausal transition. Menopause 2008; 15:105–111.
35. Kevenaar ME, Themmen AP, Rivadeneira F, et al. A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Hum Reprod 2007; 22:2382–2388.
36. Voorhuis M, Broekmans FJ, Fauser BC, et al. Genes involved in initial follicle recruitment may be associated with age at menopause. J Clin Endocrinol Metab 2011; 96:E473–479.
37. Tempfer CB, Riener EK, Keck C, et al. Polymorphisms associated with thrombophilia and vascular homeostasis and the timing of menarche and menopause in 728 white women. Menopause 2005; 12:325–330.
38. Stolk L, Zhai G, van Meurs JB, et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet 2009; 41:645–647.
39. Tempfer C, Unfried G, Zeillinger R, et al. Endothelial nitric oxide synthase gene polymorphism in women with idiopathic recurrent miscarriage. Hum Reprod 2001; 16:1644–1647.
40. Worda C, Walch K, Sator M, et al. The influence of Nos3 polymorphisms on age at menarche and natural menopause. Maturitas 2004; 49:157–162.
41. Hefler LA, Worda C, Huber JC, et al. A polymorphism of the Nos3 gene and age at natural menopause. Fertil Steril 2002; 78:1184–1186.
42. van Asselt KM, Kok HS, Peeters PH, et al. Factor V Leiden mutation accelerates the onset of natural menopause. Menopause 2003; 10:477–481.
43. Stolk L, Perry JR, Chasman DI, et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 2012; 44:260–268.
44. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013; 153:1194–1217.
45. King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302:643–646.
46. Day FR, Ruth KS, Thompson DJ, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet 2015; 47:1294–1303.
47. Foulkes WD, Shuen AY. In brief: BRCA1 and BRCA2. J Pathol 2013; 230:347–349.
48. Anamika Markin CJ, Rout MK, et al. Molecular basis for impaired DNA damage response function associated with the RAP80 DeltaE81 defect. J Biol Chem 2014; 289:12852–12862.
49. Caestecker KW, Van de Walle GR. The role of BRCA1 in DNA double-strand repair: past and present. Exp Cell Res 2013; 319:575–587.
50. Desai S, Wood-Trageser M, Matic J, et al. MCM8 and MCM9 nucleotide variants in women with primary ovarian insufficiency. J Clin Endocrinol Metab 2017; 102:576–582.
51. Lutzmann M, Grey C, Traver S, et al. MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell 2012; 47:523–534.
52. Inoue E, Mochida S, Takagi H, et al. SAD: a presynaptic kinase associated with synaptic vesicles and the active zone cytomatrix that regulates neurotransmitter release. Neuron 2006; 50:261–275.
53. Qin Y, Sun M, You L, et al. ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. Orphanet J Rare Dis 2012; 7:5.
54. Carty CL, Spencer KL, Setiawan VW, et al. Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Reprod 2013; 28:1695–1706.
55. Tkáč J, Xu G, Adhikary H, et al. HELB is a feedback inhibitor of DNA end resection. Mol Cell 2016; 61:405–418.
56. Hustedt N, Durocher D. The control of DNA repair by the cell cycle. Nat Cell Biol 2016; 19:1–9.
57. Hooft L, van der Veldt AA, Hoekstra OS, et al. Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules. Clin Endocrinol (Oxf) 2008; 68:252–257.
58. Mrschtik M, O’Prey J, Lao LY, et al. DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose. Cell Death Differ 2017; 24:1470.
59. Zhou S, Zhao L, Yi T, et al. Menopause-induced uterine epithelium atrophy results from arachidonic acid/prostaglandin E2 axis inhibition-mediated autophagic cell death. Sci Rep 2016; 6:31408.
60. Chen CT, Liu CT, Chen GK, et al. Meta-analysis of loci associated with age at natural menopause in African-American women. Hum Mol Genet 2014; 23:3327–3342.
61. Murray A, Bennett CE, Perry JR, et al. Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study. Hum Mol Genet 2011; 20:186–192.
62. He C, Murabito JM. Genome-wide association studies of age at menarche and age at natural menopause. Mol Cell Endocrinol 2014; 382:767–779.
63. Parikh H, Lyssenko V, Groop LC. Prioritizing genes for follow-up from genome wide association studies using information on gene expression in tissues relevant for type 2 diabetes mellitus. BMC Med Genomics 2009; 2:72.
64. Zhong H, Yang X, Kaplan LM, et al. Integrating pathway analysis and genetics of gene expression for genome-wide association studies. Am J Hum Genet 2010; 86:581–591.
65. Weel AE, Uitterlinden AG, Westendorp IC, et al. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab 1999; 84:3146–3150.
    Keywords:

    associated pathways; candidate genes; early menopause; fertility; GWAS

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