Journal article
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
Statens Serum Institut1
Department of Systems Biology, Technical University of Denmark2
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3
Copenhagen University Hospital Herlev and Gentofte4
University of Southern Denmark5
Bispebjerg University Hospital6
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-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), 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 x 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 gamma-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.
Language: | English |
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Publisher: | Nature Publishing Group UK |
Year: | 2014 |
Pages: | 92-97 |
Journal subtitle: | International Weekly Journal of Science |
ISSN: | 14764687 and 00280836 |
Types: | Journal article |
DOI: | 10.1038/nature13545 |
ORCIDs: | 0000-0001-8264-6785 and 0000-0003-4821-430X |
Adolescent Age Factors Alleles Body Mass Index Breast Neoplasms Calcium-Binding Proteins Cardiovascular Diseases Child DLK1 protein, human Diabetes Mellitus, Type 2 Europe Female Genetic Loci Genome-Wide Association Study Genomic Imprinting Humans Hypothalamo-Hypophyseal System Intercellular Signaling Peptides and Proteins KCNK9 protein, human MAGEL2 protein, human MKRN3 protein, human Male Membrane Proteins Menarche Obesity Ovary Parents Polymorphism, Single Nucleotide Potassium Channels, Tandem Pore Domain Proteins Quantitative Trait Loci Receptors, GABA-B Receptors, Retinoic Acid Ribonucleoproteins Ubiquitin-Protein Ligases WDR25 protein, human