Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
Author(s)
Type
Journal Article
Abstract
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
Date Issued
2014-10-02
Date Acceptance
2014-05-30
Citation
Nature, 2014, 514 (7520), pp.92-97
ISSN
0028-0836
Publisher
Nature Research
Start Page
92
End Page
97
Journal / Book Title
Nature
Volume
514
Issue
7520
Copyright Statement
©2014 Macmillan Publishers Limited. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/nature13545
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000342420800042&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CENTRAL PRECOCIOUS PUBERTY
HUMAN PREFRONTAL CORTEX
BREAST-CANCER RISK
GENE-EXPRESSION
WIDE ASSOCIATION
METAANALYSIS
DISEASE
VARIANTS
CELLS
REVEALS
Publication Status
Published
Date Publish Online
2014-07-23