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Nat Commun. 2018 May 17;9(1):1977. doi: 10.1038/s41467-018-04398-z.

Elucidating the genetic architecture of reproductive ageing in the Japanese population.

Author information

1
Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Centre for Integrative Medical Sciences, Yokohama, 230-0045, Japan. momoko.horikoshi@riken.jp.
2
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
3
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
4
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
5
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
6
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
7
Primate Genetics Section/Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, 97006, USA.
8
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, 97006, USA.
9
RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
10
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. john.perry@mrc-epid.cam.ac.uk.

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.

PMID:
29773799
PMCID:
PMC5958096
DOI:
10.1038/s41467-018-04398-z
[Indexed for MEDLINE]
Free PMC Article

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