Abstract / Summary
Abstract We analyzed genome-wide association study (GWAS) summary statistics for age at natural menopause (ANM) from 173,424 women of European ancestry and identified 230 genomic risk loci, 108 of which were novel. Fine-mapping prioritized 216 representative variants, one per fine-mapped locus, each within a 90% credible set and with posterior inclusion probability (PIP) > 0.03; 168 of these variants were novel. Integration of transcriptome-wide association analysis (TWAS), Mendelian randomization (MR), and colocalization prioritized genes with complementary functional genomic evidence. Single-cell enhancer–gene maps highlighted candidate cell-type-specific regulatory targets in brain and pituitary, including HSD17B6 in inhibitory neurons, NBR1 and HGS in oligodendrocyte precursor cells (OPCs), and ERBB4 in pituitary lactotropes. TWAS showed positive associations of genetically predicted NBR1 expression in ovary (Z = 15) and ERBB4 expression in pituitary (Z = 5.1) with ANM. MR identified associations between later ANM and higher genetically predicted expression of HSD17B6 across five brain tissues, including frontal cortex BA9 (β = 0.087), as well as higher genetically predicted expression of NBR1 in cerebellum (β = 0.095). These findings advance the interpretation of ANM genetics by prioritizing candidate variants and genes and highlighting cell-type-specific regulatory mechanisms potentially relevant to reproductive aging.