Elucidating the genetic architecture of reproductive ageing in the Japanese population

Momoko Horikoshi, Felix R. Day, Masato Akiyama, Makoto Hirata, Yoichiro Kamatani, Koichi Matsuda, Kazuyoshi Ishigaki, Masahiro Kanai, Hollis Wright, Carlos A. Toro, Sergio R. Ojeda, Alejandro Lomniczi, Michiaki Kubo, Ken K. Ong, John R.B. Perry

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Abstract

Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). 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 associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches.

Original languageEnglish
Article number1977
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Horikoshi, M., Day, F. R., Akiyama, M., Hirata, M., Kamatani, Y., Matsuda, K., ... Perry, J. R. B. (2018). Elucidating the genetic architecture of reproductive ageing in the Japanese population. Nature communications, 9(1), [1977]. https://doi.org/10.1038/s41467-018-04398-z