Rare coding variants and X-linked loci associated with age at menarche

Kathryn L Lunetta; Felix R Day; Patrick Sulem; Katherine S Ruth; Joyce Y Tung; David A Hinds; Tõnu Esko; Cathy E Elks; Elisabeth Altmaier; Chunyan He; Jennifer E Huffman; Evelin Mihailov; Eleonora Porcu; Antonietta Robino; Lynda M Rose; Ursula M Schick; Lisette Stolk; Alexander Teumer; Deborah J Thompson; Michela Traglia; Carol A Wang; Laura M Yerges-Armstrong; Antonis C Antoniou; Caterina Barbieri; Andrea D Coviello; Francesco Cucca; Ellen W Demerath; Alison M Dunning; Ilaria Gandin; Megan L Grove; Daniel F Gudbjartsson; Lynne J Hocking; Albert Hofman; Jinyan Huang; Rebecca D Jackson; David Karasik; Jennifer Kriebel; Ethan M Lange; Leslie A Lange; Claudia Langenberg; Xin Li; Jian'an Luan; Reedik Mägi; Alanna C Morrison; Sandosh Padmanabhan; Ailith Pirie; Ozren Polasek; David Porteous; Alex P Reiner; Fernando Rivadeneira; Igor Rudan; Cinzia F Sala; David Schlessinger; Robert A Scott; Doris Stöckl; Jenny A Visser; Uwe Völker; Diego Vozzi; James G Wilson; Marek Zygmunt; Eric Boerwinkle; Julie E Buring; Laura Crisponi; Douglas F Easton; Caroline Hayward; Frank B Hu; Simin Liu; Andres Metspalu; Craig E Pennell; Paul M Ridker; Konstantin Strauch; Elizabeth A Streeten; Daniela Toniolo; André G Uitterlinden; Sheila Ulivi; Henry Völzke; Nicholas J Wareham; Melissa Wellons; Nora Franceschini; Daniel I Chasman; Unnur Thorsteinsdottir; Anna Murray; Kari Stefansson; Joanne M Murabito; Ken K Ong; John R B Perry; Generation Scotland; Panos Deloukas

doi:10.1038/ncomms8756

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Rare coding variants and X-linked loci associated with age at menarche

Journal article

Open access

Peer reviewed

Rare coding variants and X-linked loci associated with age at menarche

Kathryn L Lunetta, Felix R Day, Patrick Sulem, Katherine S Ruth, Joyce Y Tung, David A Hinds, Tõnu Esko, Cathy E Elks, Elisabeth Altmaier, Chunyan He, …

Nature communications, Vol.6(1), pp.7756-7756

04/08/2015

DOI: https://doi.org/10.1038/ncomms8756

PMCID: PMC4538850

PMID: 26239645

Abstract

Adolescent

Adult

Age Factors

Aged

Amides

AMP-Activated Protein Kinases - genetics

Autoantigens - genetics

Cell Cycle Proteins

Chromosomes, Human, X - genetics

Codon, Nonsense

Energy Metabolism - genetics

Fatty Acids

Female

Gene Frequency

Genes, X-Linked - genetics

Genetic Variation

Genotype

Humans

Hypogonadism - genetics

Immunoglobulins - genetics

Laminin - genetics

Membrane Proteins - genetics

Menarche - genetics

Middle Aged

Mutation, Missense

Penetrance

Phenotype

Proteins - genetics

Receptors, Neurokinin-3 - genetics

RNA Interference

RNA-Binding Proteins - genetics

Signal Transduction - genetics

Whites - genetics

Young Adult

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

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Title: Rare coding variants and X-linked loci associated with age at menarche
Creators - without role: Kathryn L Lunetta - Boston University
Felix R Day - MRC Epidemiology Unit
Patrick Sulem - deCODE Genetics
Katherine S Ruth - University of Exeter
Joyce Y Tung - 23andMe
David A Hinds - 23andMe
Tõnu Esko - University of Tartu
Cathy E Elks - MRC Epidemiology Unit
Elisabeth Altmaier - Helmholtz Zentrum München
Chunyan He - Indiana University – Purdue University Indianapolis
Jennifer E Huffman - MRC Institute of Genetics and Molecular Medicine
Evelin Mihailov - University of Tartu
Eleonora Porcu - National Research Council
Antonietta Robino - IRCCS Materno Infantile Burlo Garofolo
Lynda M Rose - Brigham and Women's Hospital
Ursula M Schick - Fred Hutch Cancer Center
Lisette Stolk - Erasmus University Rotterdam
Alexander Teumer - Greifswald University Hospital
Deborah J Thompson - University of Cambridge
Michela Traglia - Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano 20132, Italy
Carol A Wang - University of Western Australia
Laura M Yerges-Armstrong - University of Maryland, Baltimore
Antonis C Antoniou - University of Cambridge
Caterina Barbieri - Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano 20132, Italy
Andrea D Coviello - Boston University
Francesco Cucca - National Research Council
Ellen W Demerath - Division of Epidemiology &Community Health, University of Minnesotta, Minneapolis, MN 55455, USA
Alison M Dunning - University of Cambridge
Ilaria Gandin - University of Trieste
Megan L Grove - The University of Texas Health Science Center at Houston
Daniel F Gudbjartsson - deCODE Genetics
Lynne J Hocking - University of Aberdeen
Albert Hofman - Erasmus University Rotterdam
Jinyan Huang - Shanghai Jiao Tong University
Rebecca D Jackson - The Ohio State University
David Karasik - Hebrew SeniorLife
Jennifer Kriebel - Helmholtz Zentrum München
Ethan M Lange - University of North Carolina at Chapel Hill
Leslie A Lange - University of North Carolina at Chapel Hill
Claudia Langenberg - University of Cambridge
Xin Li - Harvard University
Jian'an Luan - University of Cambridge
Reedik Mägi - University of Tartu
Alanna C Morrison - The University of Texas Health Science Center at Houston
Sandosh Padmanabhan - British Heart Foundation
Ailith Pirie - University of Cambridge
Ozren Polasek - University of Split
David Porteous - MRC Institute of Genetics and Molecular Medicine
Alex P Reiner - Fred Hutch Cancer Center
Fernando Rivadeneira - Erasmus MC
Igor Rudan - University of Edinburgh
Cinzia F Sala - Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano 20132, Italy
David Schlessinger - National Institute on Aging
Robert A Scott - MRC Epidemiology Unit
Doris Stöckl - Helmholtz Zentrum München
Jenny A Visser - Erasmus MC
Uwe Völker - Greifswald University Hospital
Diego Vozzi - IRCCS Materno Infantile Burlo Garofolo
James G Wilson - University of Mississippi Medical Center
Marek Zygmunt - Greifswald University Hospital
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Julie E Buring - Brigham and Women's Hospital
Laura Crisponi - National Research Council
Douglas F Easton - University of Cambridge
Caroline Hayward - MRC Institute of Genetics and Molecular Medicine
Frank B Hu - Brigham and Women's Hospital
Simin Liu - Brown University
Andres Metspalu - University of Tartu
Craig E Pennell - University of Western Australia
Paul M Ridker - Brigham and Women's Hospital
Konstantin Strauch - Helmholtz Zentrum München
Elizabeth A Streeten - Program in Personalized Medicine, Division of Endocrinology, Diabetes and Nutrition-University of Maryland School of Medicine, Baltimore, MD 21201, USA
Daniela Toniolo - Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano 20132, Italy
André G Uitterlinden - Erasmus MC
Sheila Ulivi - Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste 34137, Italy
Henry Völzke - Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany
Nicholas J Wareham - University of Cambridge
Melissa Wellons - Vanderbilt University Medical Center
Nora Franceschini - Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA
Daniel I Chasman - Brigham and Women's Hospital
Unnur Thorsteinsdottir - University of Iceland
Anna Murray - University of Exeter
Kari Stefansson - University of Iceland
Joanne M Murabito - Boston University School of Medicine
Ken K Ong - University of Cambridge
John R B Perry - University of Cambridge
Generation Scotland
Panos Deloukas - King Abdulaziz University
Publication Details: Nature communications, Vol.6(1), pp.7756-7756
Grant note: MC_UU_12015/1 / Medical Research Council MC_UU_12015/5 / Medical Research Council P30 CA015704 / NCI NIH HHS MC_U106179472 / Medical Research Council MC_UP_A100_1003 / Medical Research Council MC_UU_12015/2 / Medical Research Council 11174 / Cancer Research UK CZD/16/6/4 / Chief Scientist Office MC_PC_U127561128 / Medical Research Council UL1 TR001108 / NCATS NIH HHS MC_U106179471 / Medical Research Council MR/K026992/1 / Medical Research Council UM1 CA182913 / NCI NIH HHS R01 AG029451 / NIA NIH HHS R21 AG032598 / NIA NIH HHS
Identifiers: 9939437208331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article