We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; −0.4 year per T allele (39%); P = 6.3 × 10 −11 ), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10 −11 ) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10 −8 ). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.Menopause, the time of a woman's life when menstrual cycle ceases owing to depletion of the follicle pool, is a key event in reproductive aging. It influences a woman's well-being Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2010 December 10. Typical for complex quantitative traits, genome-wide linkage studies of menopause have been unsuccessful, and candidate gene studies have mainly focused on the estrogen pathway6 and have had conflicting results7. This suggests that the apparent effect sizes for genetic variants are small and that the major causative loci have not been identified. Genome-wide association studies (GWAS) have proven successful in identifying common susceptibility genes with small effect sizes for many complex diseases and traits8 and might be suitable to identify genetic factors involved in determining age at menopause.In this GWAS we used a two-stage design to identify previously unknown loci influencing age at menopause. We included women with self-reported natural age at menopause (defined as 12 months without regular periods) between 40 and 60 years, excluding those with hysterectomy, uni-or bilateral ovariectomy, menopause induced by irradiation or occurring after stopping the contraceptive pill, or those currently using hormone replacement therapy.In stage 1 we genotyped 2,368 women of the Rotterdam Study baseline9 with the Illumina HumanHap 550v3 Beadarray. After quality control, 535,354 SNPs were left for analysis. Allelic association tests were carried out using PLINKv1.01 software10 for age at natural menopause. The genomic inflation factor (λ) was 1.01669 for this analysis, indicating no population stratification, so we based our results on the uncorrected P values. The strongest association signals were found for rs2151145 (P = 5.3 × 10 −6 ) on chromosome 9, rs236114 (P = 5.6 × 10 −6 ) on chromosome 20 and rs1172822 (P = 6.3 × 10 −6 ) on chromosome 19 (Supplementary Table 1 and Supplementary Fig. 1a online).We combined the results from the Rotterdam Study baseline with GWA data from the TwinsUK study. A total of 611 women with natural menopause using the same definitions and exclusions as above were genotyped with the Illumina HumanHap 300K beadarray, and after quality control 317,818 SNPs were left for analysis. After adjusting for relatedness and genomic control, we did not observe any genome-wide significant signals in this study (Supplementary Table 1 and Supplementary...

No abstract

Our results support the role of fat mass as the primary risk marker for disability, which might later accelerate by the age-related decrease in lean mass and the development of sarcopenia after the age of 75 years.