Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. / Perry, John R B; Day, Felix; Elks, Cathy E; Sulem, Patrick; Thompson, Deborah J; Ferreira, Teresa; He, Chunyan; Chasman, Daniel I; Esko, Tõnu; Thorleifsson, Gudmar; Albrecht, Eva; Ang, Wei Q; Corre, Tanguy; Cousminer, Diana L; Feenstra, Bjarke; Franceschini, Nora; Ganna, Andrea; Johnson, Andrew D; Kjellqvist, Sanela; Lunetta, Kathryn L; McMahon, George; Nolte, Ilja M; Paternoster, Lavinia; Porcu, Eleonora; Smith, Albert V; Stolk, Lisette; Teumer, Alexander; Tšernikova, Natalia; Tikkanen, Emmi; Ulivi, Sheila; Wagner, Erin K; Amin, Najaf; Bierut, Laura J; Byrne, Enda M; Hottenga, Jouke-Jan; Koller, Daniel L; Mangino, Massimo; Pers, Tune H; Yerges-Armstrong, Laura M; Hua Zhao, Jing; Andrulis, Irene L; Anton-Culver, Hoda; Atsma, Femke; Bandinelli, Stefania; Beckmann, Matthias W; Benitez, Javier; Bojesen, Stig E; Melbye, Mads; Nohr, Ellen A; Sørensen, Thorkild I A; Australian Ovarian Cancer Study.
In: Nature, Vol. 514, No. 7520, 2014, p. 92-7.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 135780841