A large-scale candidate gene association study of age at menarche and age at natural menopause |
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| Authors: | Chunyan He Peter Kraft Daniel I Chasman Julie E Buring Constance Chen Susan E Hankinson Guillaume Paré Stephen Chanock Paul M Ridker David J Hunter |
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| Institution: | (1) Department of Public Health, Indiana University School of Medicine, Indianapolis, IN, USA;(2) Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA;(3) Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;(4) Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;(5) Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;(6) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA |
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| Abstract: | Recent genome-wide association (GWA) studies have identified several novel genetic loci associated with age at menarche and
age at natural menopause. However, the stringent significance threshold used in GWA studies potentially led to false negatives
and true associations may have been overlooked. Incorporating biologically relevant information, we examined whether common
genetic polymorphisms in candidate genes of nine groups of biologically plausible pathways and related phenotypes are associated
with age at menarche and age at natural menopause. A total of 18,862 genotyped and imputed single nucleotide polymorphisms
(SNPs) in 278 genes were assessed for their associations with these two traits among a total of 24,341 women from the Nurses’
Health Study (NHS, N = 2,287) and the Women’s Genome Health Study (WGHS, N = 22,054). Linear regression was used to assess the marginal association of each SNP with each phenotype. We adjusted for
multiple testing within each gene to identify statistically significant SNP associations at the gene level. To evaluate the
overall evidence for an excess of statistically significant gene associations over the proportion expected by chance, we applied
a one-sample test of proportion to each group of candidate genes. The steroid-hormone metabolism and biosynthesis pathway
was found significantly associated with both age at menarche and age at natural menopause (P = 0.040 and 0.011, respectively). In addition, the group of genes associated with precocious or delayed puberty was found
significantly associated with age at menarche (P = 0.013), and the group of genes involved in premature ovarian failure with age at menopause (P = 0.025). |
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