Rare coding variants in DNA damage repair genes associated with timing of natural menopause

The age of menopause is associated with fertility and disease risk, and its genetic control is of great interest. We use whole-exome sequences from 132,370 women in the UK Biobank to test for associations between rare damaging variants and age at natural menopause. Rare damaging variants in five genes are significantly associated with menopause: CHEK2 (p = 3.3 × 10^-51), DCLRE1A (p = 8.4 × 10^-13), and HELB (p = 5.7 × 10^-7) with later menopause and TOP3A (p = 7.6 × 10^-8) and CLPB (p = 8.1 × 10^-7) with earlier menopause. Two additional genes are suggestive: RAD54L (p = 2.4 × 10^-6) with later menopause and HROB (p = 2.9 × 10^-6) with earlier menopause. In a follow-up analysis of repeated questionnaires in women who were initially premenopausal, CHEK2, TOP3A, and RAD54L genotypes are associated with subsequent menopause. Consistent with previous genome-wide association studies (GWASs), six of the seven genes are involved in the DNA damage repair pathway. Phenome-wide scans across 398,569 men and women revealed that in addition to known associations with cancers and blood cell counts, rare variants in CHEK2 are also associated with increased risk for uterine fibroids, polycystic ovary syndrome, and prostate hypertrophy; these associations are not shared with higher-penetrance breast cancer genes. Causal mediation analysis suggests that approximately 8% of the breast cancer risk conferred by CHEK2 pathogenic variants after menopause is mediated through delayed menopause.