Brain and pituitary gene regulation links to the timing of natural menopause

In a preprint analyzing genomic data from 173,424 women of European ancestry, researchers investigated regulatory mechanisms influencing age at natural menopause. The authors analyzed genome-wide association summary statistics and identified 230 risk loci, of which 108 were novel. Fine-mapping prioritized 216 candidate variants, including 168 novel variants. By integrating transcriptome-wide analyses, Mendelian randomization, and colocalization, the team identified cell-type-specific gene targets in the brain and pituitary. Candidate targets included HSD17B6 in inhibitory neurons, NBR1 and HGS in oligodendrocyte precursor cells, and ERBB4 in pituitary lactotropes. Genetically predicted expression of NBR1 in the ovary and ERBB4 in the pituitary positively associated with age at natural menopause. Additionally, higher genetically predicted expression of HSD17B6 across five brain tissues, as well as NBR1 in the cerebellum, was associated with later menopause.