TY - JOUR

T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

AU - Perry, John R B

AU - Day, Felix

AU - Elks, Cathy E

AU - Sulem, Patrick

AU - Thompson, Deborah J

AU - Ferreira, Teresa

AU - He, Chunyan

AU - Chasman, Daniel I

AU - Esko, Tõnu

AU - Thorleifsson, Gudmar

AU - Albrecht, Eva

AU - Ang, Wei Q

AU - Corre, Tanguy

AU - Cousminer, Diana L

AU - Feenstra, Bjarke

AU - Franceschini, Nora

AU - Ganna, Andrea

AU - Johnson, Andrew D

AU - Kjellqvist, Sanela

AU - Lunetta, Kathryn L

AU - McMahon, George

AU - Nolte, Ilja M

AU - Paternoster, Lavinia

AU - Porcu, Eleonora

AU - Smith, Albert V

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Tšernikova, Natalia

AU - Tikkanen, Emmi

AU - Ulivi, Sheila

AU - Wagner, Erin K

AU - Amin, Najaf

AU - Bierut, Laura J

AU - Byrne, Enda M

AU - Hottenga, Jouke-Jan

AU - Koller, Daniel L

AU - Mangino, Massimo

AU - Pers, Tune H

AU - Yerges-Armstrong, Laura M

AU - Hua Zhao, Jing

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Atsma, Femke

AU - Bandinelli, Stefania

AU - Beckmann, Matthias W

AU - Benitez, Javier

AU - Bojesen, Stig E

AU - Melbye, Mads

AU - Nohr, Ellen A

AU - Sørensen, Thorkild I A

AU - Australian Ovarian Cancer Study

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Adolescent

KW - Age Factors

KW - Alleles

KW - Body Mass Index

KW - Breast Neoplasms

KW - Cardiovascular Diseases

KW - Child

KW - Diabetes Mellitus, Type 2

KW - Europe

KW - Female

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Genomic Imprinting

KW - Humans

KW - Hypothalamo-Hypophyseal System

KW - Intercellular Signaling Peptides and Proteins

KW - Male

KW - Membrane Proteins

KW - Menarche

KW - Obesity

KW - Ovary

KW - Parents

KW - Polymorphism, Single Nucleotide

KW - Potassium Channels, Tandem Pore Domain

KW - Proteins

KW - Quantitative Trait Loci

KW - Receptors, GABA-B

KW - Receptors, Retinoic Acid

KW - Ribonucleoproteins

U2 - 10.1038/nature13545

DO - 10.1038/nature13545

M3 - Journal article

C2 - 25231870

VL - 514

SP - 92

EP - 97

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7520

ER -