Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~7 0,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damageresponse (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10 −14 ), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.

Estrogen activates Alzheimer's disease genes

“…We used genomic data spanning multiple data types to cross validate our findings on estrogen loss and AD risk. We found excess deleterious singleton mutations in the ovarian failure [60,68–71] and early menopause [61,72–76] gene MCM8 (Table 2, Supplementary Table 11), providing robust support for our hypothesis that estrogen loss at menopause confers increased vulnerability to AD in women. This finding fits with previous studies that have linked surgical menopause to doubled lifetime risk for dementia [23], increased risk for AD neuropathology [22] and cognitive decline [22].…”

Association analysis between HFM1 variation and primary ovarian insufficiency in Chinese women

“…Several other meiosis-related genes have been reported to be associated with POI, including STAG3, MCM8, SYCE1 (10,22,23), which may be a part of 'cohesinopathies'. In vivo, mutations affect other meiotic cohesin subunits also result in abnormal oocyte development, like REC8, SMC1β, RAD21L (23).…”

An evolutionary compass for detecting signals of polygenic selection and mutational bias

“…), menopause onset (Day et al. ), educational attainment (Okbay et al. ), and global lipid levels (Willer et al.…”

“…2 and Table 1). We then applied our method to six additional phenotypes, which we selected to span a wide range of phenotypes that we hypothesized might be targets of selection, including body size (Wood et al 2014), psychiatric conditions (CDG Psychiatric Genomics Consortium 2013), immune-related traits (Franke et al 2010), reproductive traits (Day et al 2015), and cardiovascular traits (Willer et al 2013). We find an additional nonneutral signal for Crohn's disease, and a marginally significant signal for schizophrenia that narrowly missed a multiple testing correction (Table 1; Figs.…”