Elucidating the genetic architecture of reproductive ageing in the Japanese population

Abstract

Population studies over the past decade have successfully elucidated the genetic architecture of reproductive ageing. However, those studies were largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, in up to 67,029 women of Japanese ancestry, we report 26 loci (all P<5x10{macron}8) for puberty timing or age at menopause, representing the first loci for reproductive ageing in any non-European population. Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European populations, highlighting the benefits and challenges of large-scale trans-ethnic approaches.