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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 mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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.

Original publication

DOI

10.1038/nature13545

Type

Journal article

Journal

Nature

Publication Date

10/2014

Volume

514

Pages

92 - 97

Addresses

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Keywords

Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, Ovary, Hypothalamo-Hypophyseal System, Humans, Breast Neoplasms, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Obesity, Intercellular Signaling Peptides and Proteins, Proteins, Potassium Channels, Tandem Pore Domain, Ribonucleoproteins, Membrane Proteins, Receptors, GABA-B, Receptors, Retinoic Acid, Body Mass Index, Parents, Age Factors, Genomic Imprinting, Menarche, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Adolescent, Child, Europe, Female, Male, Genome-Wide Association Study, Genetic Loci