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

Title: Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
Authors: Perry, JRB
Day, F
Elks, CE
Sulem, P
Thompson, DJ
Ferreira, T
He, C
Chasman, DI
Esko, T
Thorleifsson, G
Albrecht, E
Ang, WQ
Corre, T
Cousminer, DL
Feenstra, B
Franceschini, N
Ganna, A
Johnson, AD
Kjellqvist, S
Lunetta, KL
McMahon, G
Nolte, IM
Paternoster, L
Porcu, E
Smith, AV
Stolk, L
Teumer, A
Tsernikova, N
Tikkanen, E
Ulivi, S
Wagner, EK
Amin, N
Bierut, LJ
Byrne, EM
Hottenga, J-J
Koller, DL
Mangino, M
Pers, TH
Yerges-Armstrong, LM
Zhao, JH
Andrulis, IL
Anton-Culver, H
Atsma, F
Bandinelli, S
Beckmann, MW
Benitez, J
Blomqvist, C
Bojesen, SE
Bolla, MK
Bonanni, B
Brauch, H
Brenner, H
Buring, JE
Chang-Claude, J
Chanock, S
Chen, J
Chenevix-Trench, G
Collee, JM
Couch, FJ
Couper, D
Coviello, AD
Cox, A
Czene, K
D'adamo, AP
Smith, GD
De Vivo, I
Demerath, EW
Dennis, J
Devilee, P
Dieffenbach, AK
Dunning, AM
Eiriksdottir, G
Eriksson, JG
Fasching, PA
Ferrucci, L
Flesch-Janys, D
Flyger, H
Foroud, T
Franke, L
Garcia, ME
Garcia-Closas, M
Geller, F
De Geus, EEJ
Giles, GG
Gudbjartsson, DF
Gudnason, V
Guenel, P
Guo, S
Hall, P
Hamann, U
Haring, R
Hartman, CA
Heath, A
Hofman, A
Hooning, MJ
Hopper, JL
Hu, FB
Hunter, DJ
Karasik, D
Kiel, DP
Knight, JA
Kosma, V-M
Kutalik, Z
Lai, S
Lambrechts, D
Lindblom, A
Maegi, R
Magnusson, PK
Mannermaa, A
Martin, NG
Masson, G
McArdle, PF
McArdle, WL
Melbye, M
Michailidou, K
Mihailov, E
Milani, L
Milne, RL
Nevanlinna, H
Neven, P
Nohr, EA
Oldehinkel, AJ
Oostra, BA
Palotie, A
Peacock, M
Pedersen, NL
Peterlongo, P
Peto, J
Pharoah, PDP
Postma, DS
Pouta, A
Pylkaes, K
Radice, P
Ring, S
Rivadeneira, F
Robino, A
Rose, LM
Rudolph, A
Salomaa, V
Sanna, S
Schlessinger, D
Schmidt, MK
Southey, MC
Sovio, U
Stampfer, MJ
Stoeckl, D
Storniolo, AM
Timpson, NJ
Tyrer, J
Visser, JA
Vollenweider, P
Voelzke, H
Waeber, G
Waldenberger, M
Wallaschofski, H
Wang, Q
Willemsen, G
Winqvist, R
Wolffenbuttel, BHR
Wright, MJ
Boomsma, DI
Econs, MJ
Khaw, K-T
Loos, RJF
McCarthy, MI
Montgomery, GW
Rice, JP
Streeten, EA
Thorsteinsdottir, U
Van Duijn, CM
Alizadeh, BZ
Bergmann, S
Boerwinkle, E
Boyd, HA
Crisponi, L
Gasparini, P
Gieger, C
Harris, TB
Ingelsson, E
Jaervelin, M-R
Kraft, P
Lawlor, D
Metspalu, A
Pennell, CE
Ridker, PM
Snieder, H
Sorensen, TIA
Spector, TD
Strachan, DP
Uitterlinden, AG
Wareham, NJ
Widen, E
Zygmunt, M
Murray, A
Easton, DF
Stefansson, K
Murabito, JM
Ong, KK
Item 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.
Issue Date: 2-Oct-2014
Date of Acceptance: 30-May-2014
URI: http://hdl.handle.net/10044/1/85655
DOI: 10.1038/nature13545
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
Keywords: 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
Adolescent
Age Factors
Alleles
Body Mass Index
Breast Neoplasms
Calcium-Binding Proteins
Cardiovascular Diseases
Child
Diabetes Mellitus, Type 2
Europe
Female
Genetic Loci
Genome-Wide Association Study
Genomic Imprinting
Humans
Hypothalamo-Hypophyseal System
Intercellular Signaling Peptides and Proteins
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
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
Ubiquitin-Protein Ligases
Intercellular Signaling Peptides and Proteins
Proteins
Calcium-Binding 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
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
General Science & Technology
Publication Status: Published
Online Publication Date: 2014-07-23
Appears in Collections:School of Public Health