Elucidating the genetic architecture of reproductive ageing in the Japanese population

Nature Communications
Momoko HorikoshiJohn R B Perry

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.

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Citations

May 22, 2020·Molecular Biology and Evolution·Hugo ZebergSvante Pääbo
Oct 23, 2018·NPJ Genomic Medicine·Rahul GajbhiyeGrant W Montgomery
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Aug 6, 2021·Nature·Katherine S RuthJohn R B Perry

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Datasets Mentioned

BETA
GSE94080

Methods Mentioned

BETA
RNA-seq
PCR
hormone replacement treatment
genotyping
chip

Software Mentioned

Trimmomatic
FastQC
mach2dat
Eagle2
LMM
BOLT
mach2qtl
minimac3
Rsubread featureCounts R
ONE

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