Evaluating GWAS-Identified SNPs for Age at Natural Menopause among Chinese Women

et al. (2013) Evaluating GWAS-Identified SNPs for Age at Natural Menopause among Chinese Women. PLoS ONE 8(3): e58766. doi:10.1371/journal.pone.0058766 Evaluating GWAS-Identified SNPs for Age at Natural Menopause among Chinese Women Chong Shen 0 Ryan J. Delahanty 0 Yu-Tang Gao 0 Wei Lu 0 Yong-Bing Xiang 0 Ying Zheng 0 Qiuyin Cai 0 Wei Zheng 0 Xiao-Ou Shu 0 Jirong Long 0 John R.B Perry, Peninsula College of Medicine and Dentistry, United Kingdom 0 1 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 2 Visiting from the School of Public Health, Nanjing Medical University , Nanjing , China , 3 Department of Epidemiology, Shanghai Cancer Institute , Shanghai , China , 4 Shanghai Municipal Center for Disease Prevention and Control, Shanghai Institute of Preventive Medicine , Shanghai , China Background: Age at natural menopause (ANM) is a complex trait with high heritability and is associated with several major hormonal-related diseases. Recently, several genome-wide association studies (GWAS), conducted exclusively among women of European ancestry, have discovered dozens of genetic loci influencing ANM. No study has been conducted to evaluate whether these findings can be generalized to Chinese women. Methodology/Principal Findings: We evaluated the index single nucleotide polymorphisms (SNPs) in 19 GWAS-identified genetic susceptibility loci for ANM among 3,533 Chinese women who had natural menopause. We also investigated 3 additional SNPs which were in LD with the index SNP in European-ancestry but not in Asian-ancestry populations. Two genetic risk scores (GRS) were calculated to summarize SNPs across multiple loci one for all SNPs tested (GRSall), and one for SNPs which showed association in our study (GRSsel). All 22 SNPs showed the same association direction as previously reported. Eight SNPs were nominally statistically significant with P#0.05: rs4246511 (RHBDL2), rs12461110 (NLRP11), rs2307449 (POLG), rs12611091 (BRSK1), rs1172822 (BRSK1), rs365132 (UIMC1), rs2720044 (ASH2L), and rs7246479 (TMEM150B). Especially, SNPs rs4246511, rs365132, rs1172822, and rs7246479 remained significant even after Bonferroni correction. Significant associations were observed for GRS. Women in the highest quartile began menopause 0.7 years (P = 3.2461029) and 0.9 years (P = 4.61610211) later than those in the lowest quartile for GRSsel and GRSall, respectively. Conclusions: Among the 22 investigated SNPs, eight showed associations with ANM (P,0.05) in our Chinese population. Results from this study extend some recent GWAS findings to the Asian-ancestry population and may guide future efforts to identify genetic determination of menopause. - Competing Interests: The authors have declared that no competing interests exist. The occurrence and timing of menarche and menopause play major roles in a womans life and reproduction-related events. Menopause is the final reproductive event and unambiguously marks the ovarian aging and exhaustion of the primordial follicle pool in women [1]. Menopause at a younger age often predicts an earlier induction of subfertility, sterility, and transition to cycle irregularity and vice versa [2]. Generally, age at natural menopause (ANM) ranges between 4060 years with a median of 49 to 52 years, depending on the population [3]. Population-based studies report that the beginning of transition from regular to irregular menstrual cycles is 67 years ahead of ANM. This probably reflects the end of female fertility, which is nearly 10 years ahead of ANM [4]. Menopause age variation influences the levels of serum estrogen, follicle stimulating hormone, and progesterone, all which affect the well-being of women. Series studies report that the variation of menopause is associated with several major age-related diseases [5], such as cardiovascular disease [6,7], breast cancer [8], osteoporosis [9], and depression [10]. So, identifying factors which determine variations of ANM may provide insights into the pathogenesis of these diseases. ANM is a complex trait, influenced by multiple environmental and genetic factors [11]. ANM has high heritability (70%). Genome-wide association studies (GWAS) have identified multiple genetic loci which influence ANM [1216]. All of these GWAS were exclusively conducted in European-ancestry populations. Given the considerable differences in genetic architecture including allele frequencies, linkage disequilibrium (LD) structure and genetic diversity across ethnic groups, it is important to investigate whether GWAS-identified variants are associated with ANM in Age at natural menopause Table 1. Characteristics of study participants. Number of live birth High profession/College+ Ever take oral contraceptives Age at menarche (years) Endometrial cancer Upper GI cancer Type 2 diabetes non-European populations. In this current study, we report a systematic evaluation of the GWAS-identified loci in association with ANM among Chinese. Methods Study Participants and Data Collection This analysis included women from Shanghai, China, who were participants in multiple ongoing GWAS: the Shanghai Breast Cancer Genetics Study (SBCGS) [17], the Shanghai Endometrial Cancer Genetics Study (SECGS) [18], the Shanghai Diabetes Genetics Study (SDGS) [19], the Shanghai Colorectal Cancer Genetics Study [20], the Upper GI Cancer Genetics Study, and the Panscan Cancer Genetics Study [21]. Among these studies, 4,106 reported detailed information of menopause. We excluded 573 women including 390 individuals whose menopause were disease-related, 158 individuals who took hormone replacement treatment, and 25 individuals with other non-nature cause menopause. Thus, 3,533 post-menopausal women were finally included in this study. All parent studies are population-based and similar study protocols were used across studies to collect blood or buccal cell samples and relevant exposure information. Interviews were conducted in-person, and structured epidemiological questionnaires were administered by trained interviewers. Age at natural menopause (ANM) is defined as the age when menstrual periods Chrd Position Reported studies Shanghai population Reference/Effect EAFe 0.488 0.228 0.491 0.39 0.491 0.165 0.178 0.262 0.187 0.240 1.02610216 0.612 0.287 20.164 8.46610210 0.235 20.175 8.40610214 0.139 20.196 2.21610214 0.070 20.213 1.45610259 0.336 0.386 0.144 1.80610219 0.658 0.111 2.60610212 0.504 0.284 7.76610212 0.677 0.166 2.47610219 0.662 0.071 0.265 0.225 0.036 0.085 0.174 0.225 2.25610212 0.102 0.060 20.380 3.56610213 0.274 0.334 0.170 0.120 0.520 9.31610215 0.038 0.013 2.38610219 0.038 20.184 9.53610211 0.341 0.482 0.168 1.01610211 0.847 0.188 20.158 8.74610210 0.293 0.480 0.330 0.480 0.360 1.10610210 0.773 0.285 2.5061028 0.095 2.90610212 0.815 0.487 6.6461025 0.978 Y 3.7561025 0.993 Y Power (...truncated)