The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Authors:
Dr Anubha Mahajan, PhD
Dr Anubha Mahajan, PhD
Wellcome Trust Centre for Human Genetics, University of Oxford
UK
Thomas W Winkler Anne E Justice Mariaelisa Graff Llilda Barata Mary F Feitosa Su Chu Jacek Czajkowski Tõnu Esko Tove Fall Tuomas O Kilpeläinen Yingchang Lu Reedik Mägi Evelin Mihailov Tune H Pers Sina Rüeger Alexander Teumer Georg B Ehret Teresa Ferreira Nancy L Heard-Costa Juha Karjalainen Vasiliki Lagou Michael D Neinast Inga Prokopenko Jeannette Simino Tanya M Teslovich Rick Jansen Harm-Jan Westra Charles C White Devin Absher Tarunveer S Ahluwalia Shafqat Ahmad Eva Albrecht Alexessander Couto Alves Jennifer L Bragg-Gresham Anton J M de Craen Joshua C Bis Amélie Bonnefond Gabrielle Boucher Gemma Cadby Yu-Ching Cheng Charleston W K Chiang Graciela Delgado Ayse Demirkan Nicole Dueker Niina Eklund Gudny Eiriksdottir Joel Eriksson Bjarke Feenstra Krista Fischer Francesca Frau Tessel E Galesloot Frank Geller Anuj Goel Mathias Gorski Tanja B Grammer Stefan Gustafsson Saskia Haitjema Jouke-Jan Hottenga Jennifer E Huffman Anne U Jackson Kevin B Jacobs Åsa Johansson Marika Kaakinen Marcus E Kleber Jari Lahti Irene Mateo Leach Benjamin Lehne Youfang Liu Ken Sin Lo Mattias Lorentzon Jian'an Luan Pamela A F Madden Massimo Mangino Barbara McKnight Carolina Medina-Gomez Keri L Monda May E Montasser Gabriele Müller Martina Müller-Nurasyid Ilja M Nolte Kalliope Panoutsopoulou Laura Pascoe Lavinia Paternoster Nigel W Rayner Frida Renström Federica Rizzi Lynda M Rose Kathy A Ryan Perttu Salo Serena Sanna Hubert Scharnagl Jianxin Shi Albert Vernon Smith Lorraine Southam Alena Stančáková Valgerdur Steinthorsdottir Rona J Strawbridge Yun Ju Sung Ioanna Tachmazidou Toshiko Tanaka Gudmar Thorleifsson Stella Trompet Natalia Pervjakova Jonathan P Tyrer Liesbeth Vandenput Sander W van der Laan Nathalie van der Velde Jessica van Setten Jana V van Vliet-Ostaptchouk Niek Verweij Efthymia Vlachopoulou Lindsay L Waite Sophie R Wang Zhaoming Wang Sarah H Wild Christina Willenborg James F Wilson Andrew Wong Jian Yang Loïc Yengo Laura M Yerges-Armstrong Lei Yu Weihua Zhang Jing Hua Zhao Ehm A Andersson Stephan J L Bakker Damiano Baldassarre Karina Banasik Matteo Barcella Cristina Barlassina Claire Bellis Paola Benaglio John Blangero Matthias Blüher Fabrice Bonnet Lori L Bonnycastle Heather A Boyd Marcel Bruinenberg Aron S Buchman Harry Campbell Yii-Der Ida Chen Peter S Chines Simone Claudi-Boehm John Cole Francis S Collins Eco J C de Geus Lisette C P G M de Groot Maria Dimitriou Jubao Duan Stefan Enroth Elodie Eury Aliki-Eleni Farmaki Nita G Forouhi Nele Friedrich Pablo V Gejman Bruna Gigante Nicola Glorioso Alan S Go Omri Gottesman Jürgen Gräßler Harald Grallert Niels Grarup Yu-Mei Gu Linda Broer Annelies C Ham Torben Hansen Tamara B Harris Catharina A Hartman Maija Hassinen Nicholas Hastie Andrew T Hattersley Andrew C Heath Anjali K Henders Dena Hernandez Hans Hillege Oddgeir Holmen Kees G Hovingh Jennie Hui Lise L Husemoen Nina Hutri-Kähönen Pirro G Hysi Thomas Illig Philip L De Jager Shapour Jalilzadeh Torben Jørgensen J Wouter Jukema Markus Juonala Stavroula Kanoni Maria Karaleftheri Kay Tee Khaw Leena Kinnunen Steven J Kittner Wolfgang Koenig Ivana Kolcic Peter Kovacs Nikolaj T Krarup Wolfgang Kratzer Janine Krüger Diana Kuh Meena Kumari Theodosios Kyriakou Claudia Langenberg Lars Lannfelt Chiara Lanzani Vaneet Lotay Lenore J Launer Karin Leander Jaana Lindström Allan Linneberg Yan-Ping Liu Stéphane Lobbens Robert Luben Valeriya Lyssenko Satu Männistö Patrik K Magnusson Wendy L McArdle Cristina Menni Sigrun Merger Lili Milani Grant W Montgomery Andrew P Morris Narisu Narisu Mari Nelis Ken K Ong Aarno Palotie Louis Pérusse Irene Pichler Maria G Pilia Anneli Pouta Myriam Rheinberger Rasmus Ribel-Madsen Marcus Richards Kenneth M Rice Treva K Rice Carlo Rivolta Veikko Salomaa Alan R Sanders Mark A Sarzynski Salome Scholtens Robert A Scott William R Scott Sylvain Sebert Sebanti Sengupta Bengt Sennblad Thomas Seufferlein Angela Silveira P Eline Slagboom Jan H Smit Thomas H Sparsø Kathleen Stirrups Ronald P Stolk Heather M Stringham Morris A Swertz Amy J Swift Ann-Christine Syvänen Sian-Tsung Tan Barbara Thorand Anke Tönjes Angelo Tremblay Emmanouil Tsafantakis Peter J van der Most Uwe Völker Marie-Claude Vohl Judith M Vonk Melanie Waldenberger Ryan W Walker Roman Wennauer Elisabeth Widén Gonneke Willemsen Tom Wilsgaard Alan F Wright M Carola Zillikens Suzanne C van Dijk Natasja M van Schoor Folkert W Asselbergs Paul I W de Bakker Jacques S Beckmann John Beilby David A Bennett Richard N Bergman Sven Bergmann Carsten A Böger Bernhard O Boehm Eric Boerwinkle Dorret I Boomsma Stefan R Bornstein Erwin P Bottinger Claude Bouchard John C Chambers Stephen J Chanock Daniel I Chasman Francesco Cucca Daniele Cusi George Dedoussis Jeanette Erdmann Johan G Eriksson Denis A Evans Ulf de Faire Martin Farrall Luigi Ferrucci Ian Ford Lude Franke Paul W Franks Philippe Froguel Ron T Gansevoort Christian Gieger Henrik Grönberg Vilmundur Gudnason Ulf Gyllensten Per Hall Anders Hamsten Pim van der Harst Caroline Hayward Markku Heliövaara Christian Hengstenberg Andrew A Hicks Aroon Hingorani Albert Hofman Frank Hu Heikki V Huikuri Kristian Hveem Alan L James Joanne M Jordan Antti Jula Mika Kähönen Eero Kajantie Sekar Kathiresan Lambertus A L M Kiemeney Mika Kivimaki Paul B Knekt Heikki A Koistinen Jaspal S Kooner Seppo Koskinen Johanna Kuusisto Winfried Maerz Nicholas G Martin Markku Laakso Timo A Lakka Terho Lehtimäki Guillaume Lettre Douglas F Levinson Lars Lind Marja-Liisa Lokki Pekka Mäntyselkä Mads Melbye Andres Metspalu Braxton D Mitchell Frans L Moll Jeffrey C Murray Arthur W Musk Markku S Nieminen Inger Njølstad Claes Ohlsson Albertine J Oldehinkel Ben A Oostra Lyle J Palmer James S Pankow Gerard Pasterkamp Nancy L Pedersen Oluf Pedersen Brenda W Penninx Markus Perola Annette Peters Ozren Polašek Peter P Pramstaller Bruce M Psaty Lu Qi Thomas Quertermous Olli T Raitakari Tuomo Rankinen Rainer Rauramaa Paul M Ridker John D Rioux Fernando Rivadeneira Jerome I Rotter Igor Rudan Hester M den Ruijter Juha Saltevo Naveed Sattar Heribert Schunkert Peter E H Schwarz Alan R Shuldiner Juha Sinisalo Harold Snieder Thorkild I A Sørensen Tim D Spector Jan A Staessen Bandinelli Stefania Unnur Thorsteinsdottir Michael Stumvoll Jean-Claude Tardif Elena Tremoli Jaakko Tuomilehto André G Uitterlinden Matti Uusitupa André L M Verbeek Sita H Vermeulen Jorma S Viikari Veronique Vitart Henry Völzke Peter Vollenweider Gérard Waeber Mark Walker Henri Wallaschofski Nicholas J Wareham Hugh Watkins Eleftheria Zeggini Aravinda Chakravarti Deborah J Clegg L Adrienne Cupples Penny Gordon-Larsen Cashell E Jaquish D C Rao Goncalo R Abecasis Themistocles L Assimes Inês Barroso Sonja I Berndt Michael Boehnke Panos Deloukas Caroline S Fox Leif C Groop David J Hunter Erik Ingelsson Robert C Kaplan Mark I McCarthy Karen L Mohlke Jeffrey R O'Connell David Schlessinger David P Strachan Kari Stefansson Cornelia M van Duijn Joel N Hirschhorn Cecilia M Lindgren Iris M Heid Kari E North Ingrid B Borecki Zoltán Kutalik Ruth J F Loos

PLoS Genet 2015 Oct 1;11(10):e1005378. Epub 2015 Oct 1.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

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http://dx.doi.org/10.1371/journal.pgen.1005378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591371PMC
October 2015
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