Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

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Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5x10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

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Authors
  • Joshua C. Randall
  • Thomas W. Winkler
  • Zoltan Kutalik
  • Sonja I. Berndt
  • Anne U. Jackson
  • Keri L. Monda
  • Tuomas O. Kilpelaeinen
  • Tonu Esko
  • Reedik Maegi
  • Shengxu Li
  • Tsegaselassie Workalemahu
  • Mary F. Feitosa
  • Damien C. Croteau-Chonka
  • Felix R. Day
  • Tove Fall
  • Teresa Ferreira
  • Stefan Gustafsson
  • Adam E. Locke
  • Iain Mathieson
  • Andre Scherag
  • Sailaja Vedantam
  • Andrew R. Wood
  • Liming Liang
  • Valgerdur Steinthorsdottir
  • Gudmar Thorleifsson
  • Emmanouil T. Dermitzakis
  • Antigone S. Dimas
  • Fredrik Karpe
  • Josine L. Min
  • George Nicholson
  • Deborah J. Clegg
  • Thomas Person
  • Jon P. Krohn
  • Sabrina Bauer
  • Christa Buechler
  • Kristina Eisinger
  • Amelie Bonnefond
  • Philippe Froguel
  • Jouke-Jan Hottenga
  • Inga Prokopenko
  • Lindsay L. Waite
  • Tamara B. Harris
  • Albert Vernon Smith
  • Alan R. Shuldiner
  • Wendy L. McArdle
  • Mark J. Caulfield
  • Patricia B. Munroe
  • Henrik Gronberg
  • Yii-Der Ida Chen
  • Guo Li
  • Jacques S. Beckmann
  • Toby Johnson
  • Unnur Thorsteinsdottir
  • Maris Teder-Laving
  • Kay-Tee Khaw
  • Nicholas J. Wareham
  • Jing Hua Zhao
  • Najaf Amin
  • Ben A. Oostra
  • Aldi T. Kraja
  • Michael A. Province
  • L. Adrienne Cupples
  • Nancy L. Heard-Costa
  • Jaakko Kaprio
  • Samuli Ripatti
  • Ida Surakka
  • Francis S. Collins
  • Jouko Saramies
  • Jaakko Tuomilehto
  • Antti Jula
  • Veikko Salomaa
  • Jeanette Erdmann
  • Christian Hengstenberg
  • Christina Loley
  • Heribert Schunkert
  • Claudia Lamina
  • H. Erich Wichmann
  • Eva Albrecht
  • Christian Gieger
  • Andrew A. Hicks
  • Asa Johansson
  • Peter P. Pramstaller
  • Sekar Kathiresan
  • Elizabeth K. Speliotes
  • Brenda Penninx
  • Anna-Liisa Hartikainen
  • Marjo-Riitta Jarvelin
  • Ulf Gyllensten
  • Dorret I. Boomsma
  • Harry Campbell
  • James F. Wilson
  • Stephen J. Chanock
  • Martin Farrall
  • Anuj Goel
  • Carolina Medina-Gomez
  • Fernando Rivadeneira
  • Karol Estrada
  • Andre G. Uitterlinden
  • Albert Hofman
  • M. Carola Zillikens
  • Martin den Heijer
  • Lambertus A. Kiemeney
  • Andrea Maschio
  • Per Hall
  • Jonathan Tyrer
  • Alexander Teumer
  • Henry Voelzke
  • Peter Kovacs
  • Anke Toenjes
  • Massimo Mangino
  • Tim D. Spector
  • Caroline Hayward
  • Igor Rudan
  • Alistair S. Hall
  • Nilesh J. Samani
  • Antony Paul Attwood
  • Jennifer G. Sambrook
  • Joseph Hung
  • Lyle J. Palmer
  • Marja-Liisa Lokki
  • Juha Sinisalo
  • Gabrielle Boucher
  • Heikki Huikuri
  • Mattias Lorentzon
  • Claes Ohlsson
  • Niina Eklund
  • Johan G. Eriksson
  • Cristina Barlassina
  • Carlo Rivolta
  • Ilja M. Nolte
  • Harold Snieder
  • Melanie M. Van der Klauw
  • Jana V. Van Vliet-Ostaptchouk
  • Pablo V. Gejman
  • Jianxin Shi
  • Kevin B. Jacobs
  • Zhaoming Wang
  • Stephan J. L. Bakker
  • Irene Mateo Leach
  • Gerjan Navis
  • Pim van der Harst
  • Nicholas G. Martin
  • Sarah E. Medland
  • Grant W. Montgomery
  • Jian Yang
  • Daniel I. Chasman
  • Paul M. Ridker
  • Lynda M. Rose
  • Terho Lehtimaki
  • Olli Raitakari
  • Devin Absher
  • Carlos Iribarren
  • Hanneke Basart
  • Kees G. Hovingh
  • Elina Hyppoenen
  • Chris Power
  • Denise Anderson
  • John P. Beilby
  • Jennie Hui
  • Jennifer Jolley
  • Hendrik Sager
  • Stefan R. Bornstein
  • Peter E. H. Schwarz
  • Kati Kristiansson
  • Markus Perola
  • Jaana Lindstrom
  • Amy J. Swift
  • Matti Uusitupa
  • Mustafa Atalay
  • Timo A. Lakka
  • Rainer Rauramaa
  • Jennifer L. Bolton
  • Gerry Fowkes
  • Ross M. Fraser
  • Jackie F. Price
  • Krista Fischer
  • Kaarel KrjutAikov
  • Andres Metspalu
  • Evelin Mihailov
  • Claudia Langenberg
  • Jian'an Luan
  • Ken K. Ong
  • Peter S. Chines
  • Sirkka M. Keinanen-Kiukaanniemi
  • Timo E. Saaristo
  • Sarah Edkins
  • Goran Hallmans
  • Dmitry Shungin
  • Andrew David Morris
  • Colin N. A. Palmer
  • Raimund Erbel
  • Susanne Moebus
  • Markus M. Noethen
  • Sonali Pechlivanis
  • Kristian Hveem
  • Narisu Narisu
  • Anders Hamsten
  • Steve E. Humphries
  • Rona J. Strawbridge
  • Elena Tremoli
  • Harald Grallert
  • Barbara Thorand
  • Thomas Illig
  • Wolfgang Koenig
  • Martina Mueller-Nurasyid
  • Annette Peters
  • Bernhard O. Boehm
  • Marcus E. Kleber
  • Winfried Maerz
  • Bernhard R. Winkelmann
  • Johanna Kuusisto
  • Markku Laakso
  • Dominique Arveiler
  • Giancarlo Cesana
  • Kari Kuulasmaa
  • Jarmo Virtamo
  • John W. G. Yarnell
  • Diana Kuh
  • Andrew Wong
  • Lars Lind
  • Ulf de Faire
  • Bruna Gigante
  • Patrik K. E. Magnusson
  • Nancy L. Pedersen
  • George Dedoussis
  • Maria Dimitriou
  • Genovefa Kolovou
  • Stavroula Kanoni
  • Kathleen Stirrups
  • Lori L. Bonnycastle
  • Inger Njolstad
  • Tom Wilsgaard
  • Andrea Ganna
  • Emil Rehnberg
  • Aroon Hingorani
  • Mika Kivimaki
  • Meena Kumari
  • Themistocles L. Assimes
  • Ine S. Barroso
  • Michael Boehnke
  • Ingrid B. Borecki
  • Panos Deloukas
  • Caroline S. Fox
  • Timothy Frayling
  • Talin Haritunians
  • David Hunter
  • Erik Ingelsson
  • Robert Kaplan
  • Karen L. Mohlke
  • Jeffrey R. O'Connell
  • David Schlessinger
  • David P. Strachan
  • Kari Stefansson
  • Cornelia M. van Duijn
  • Goncalo R. Abecasis
  • Mark I. McCarthy
  • Joel N. Hirschhorn
  • Lu Qi
  • Ruth J. F. Loos
  • Cecilia M. Lindgren
  • Kari E. North
  • Iris M. Heid
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Article numbere1003500
JournalPLoS Genetics
Volume9
Issue number6
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes

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