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

Thomas W Winkler , Anne E Justice , Mariaelisa Graff , Llilda Barata , Mary F Feitosa (1) , Su Chu (2) , Jacek Czajkowski , Tõnu Esko (3, 4) , Tove Fall (5) , Tuomas O Kilpeläinen (6) , Yingchang Lu (7) , Reedik Mägi , Evelin Mihailov , Tune H Pers (8) , Sina Rüeger , Alexander Teumer (9) , Georg B Ehret , Teresa Ferreira , Nancy L Heard-Costa , Juha Karjalainen , Vasiliki Lagou , Anubha Mahajan , Michael D Neinast , Inga Prokopenko , Jeannette Simino , Tanya M Teslovich , Rick Jansen (10) , Harm-Jan Westra , Charles C White (11) , Devin Absher , Tarunveer S Ahluwalia , Shafqat Ahmad (12) , Eva Albrecht , Alexessander Couto Alves , Jennifer L Bragg-Gresham (13) , Anton J M de Craen (14) , Joshua C Bis (15) , Amélie Bonnefond (16) , Gabrielle Boucher , Gemma Cadby , Yu-Ching Cheng , Charleston W K Chiang , Graciela Delgado , Ayse Demirkan (17) , Nicole Dueker , Niina Eklund , Gudny Eiriksdottir , Joel Eriksson (18) , Bjarke Feenstra , Krista Fischer (19) , Francesca Frau , Tessel E Galesloot , Frank Geller , Anuj Goel , Mathias Gorski , Tanja B Grammer , Stefan Gustafsson (20) , Saskia Haitjema , Jouke-Jan Hottenga (9) , Jennifer E Huffman , Anne U Jackson (21) , Kevin B Jacobs (22, 23) , Åsa Johansson , Marika Kaakinen (24) , Marcus E Kleber , Jari Lahti , Irene Mateo Leach , Benjamin Lehne , Youfang Liu , Ken Sin Lo (25) , Mattias Lorentzon , Jian'An Luan , Pamela a F Madden (26) , Massimo Mangino (9) , Barbara Mcknight , Carolina Medina-Gomez , Keri L Monda (27) , May E Montasser , Gabriele Müller , Martina Müller-Nurasyid , Ilja M Nolte (9) , Kalliope Panoutsopoulou (28) , Laura Pascoe , Lavinia Paternoster , Nigel W Rayner (28) , Frida Renström (29, 30, 31) , Federica Rizzi , Lynda M Rose , Kathy A Ryan , Perttu Salo , Serena Sanna , Hubert Scharnagl , Jianxin Shi , Albert Vernon Smith , Lorraine Southam (28) , Alena Stančáková (32) , Valgerdur Steinthorsdottir , Rona J Strawbridge (33) , Yun Ju Sung (34) , Ioanna Tachmazidou , Toshiko Tanaka (35) , Gudmar Thorleifsson (36) , Stella Trompet (37) , Natalia Pervjakova , Jonathan P Tyrer , Liesbeth Vandenput , Sander W van Der Laan , Nathalie van Der Velde , Jessica van Setten , Jana V van Vliet-Ostaptchouk (38) , 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 (16) , Laura M Yerges-Armstrong , Lei Yu , Weihua Zhang , Jing Hua Zhao , Ehm A Andersson , Stephan J L Bakker (39) , Damiano Baldassarre , Karina Banasik , Matteo Barcella , Cristina Barlassina , Claire Bellis , Paola Benaglio , John Blangero (40, 41) , Matthias Blüher (42) , Fabrice Bonnet (43) , Lori L Bonnycastle , Heather A Boyd (44) , Marcel Bruinenberg , Aron S Buchman , Harry Campbell (45) , Yii-Der Ida Chen , Peter S Chines , Simone Claudi-Boehm , John Cole (46) , Francis S Collins , Eco J C de Geus (47) , Lisette C P G M de Groot , Maria Dimitriou , Jubao Duan (48) , Stefan Enroth , Elodie Eury (16) , Aliki-Eleni Farmaki , Nita G Forouhi (49) , Nele Friedrich , Pablo V Gejman , Bruna Gigante , Nicola Glorioso , Alan S Go , Omri Gottesman , Jürgen Grässler , Harald Grallert (50) , Niels Grarup (51) , Yu-Mei Gu (52) , Linda Broer (9) , Annelies C Ham , Torben Hansen (51) , Tamara B Harris , Catharina A Hartman (47) , Maija Hassinen , Nicholas Hastie , Andrew T Hattersley , Andrew C Heath , Anjali K Henders , Dena Hernandez (53) , Hans Hillege (54) , Oddgeir Holmen , Kees G Hovingh , Jennie Hui , Lise L Husemoen , Nina Hutri-Kähönen , Pirro G Hysi , Thomas Illig (55) , Philip L de Jager (56, 57, 58) , Shapour Jalilzadeh , Torben Jørgensen (59, 60, 61) , J Wouter Jukema (37) , Markus Juonala , Stavroula Kanoni (62) , Maria Karaleftheri , Kay Tee Khaw , Leena Kinnunen , Steven J Kittner , Wolfgang Koenig , Ivana Kolcic (63) , Peter Kovacs , Nikolaj T Krarup , Wolfgang Kratzer , Janine Krüger , Diana Kuh (64) , Meena Kumari (65) , Theodosios Kyriakou , Claudia Langenberg (49) , Lars Lannfelt (66) , Chiara Lanzani , Vaneet Lotay , Lenore J Launer , Karin Leander , Jaana Lindström , Allan Linneberg (67) , Yan-Ping Liu , Stéphane Lobbens (68) , Robert Luben (69) , Valeriya Lyssenko , Satu Männistö (70) , Patrik K Magnusson , Wendy L Mcardle , Cristina Menni , Sigrun Merger , Lili Milani , Grant W Montgomery (71, 17) , Andrew P Morris , Narisu Narisu , Mari Nelis , Ken K Ong (72) , Aarno Palotie (73) , Louis Pérusse (31) , Irene Pichler , Maria G Pilia , Anneli Pouta , Myriam Rheinberger , Rasmus Ribel-Madsen , Marcus Richards (74) , Kenneth M Rice (75) , Treva K Rice , Carlo Rivolta , Veikko Salomaa (76) , 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 (77) , Jan H Smit , Thomas H Sparsø , Kathleen Stirrups , Ronald P Stolk , Heather M Stringham (13) , Morris A Swertz (78) , Amy J Swift , Ann-Christine Syvänen (79) , Sian-Tsung Tan , Barbara Thorand (50) , Anke Tönjes , Angelo Tremblay (80) , Emmanouil Tsafantakis , Peter J van Der Most , Uwe Völker (81) , Marie-Claude Vohl , Judith M Vonk , Melanie Waldenberger , Ryan W Walker , Roman Wennauer , Elisabeth Widén (47) , Gonneke Willemsen (17) , Tom Wilsgaard , Alan F Wright , M Carola Zillikens (82, 83) , Suzanne C van Dijk , Natasja M van Schoor , Folkert W Asselbergs , Paul I W de Bakker , Jacques S Beckmann (84) , John Beilby , David A Bennett (85) , Richard N Bergman , Sven Bergmann (86) , Carsten A Böger , Bernhard O Boehm , Eric Boerwinkle (40) , Dorret I Boomsma (9) , Stefan R Bornstein (87) , Erwin P Bottinger , Claude Bouchard , John C Chambers (88) , Stephen J Chanock (23) , Daniel I Chasman (89) , Francesco Cucca , Daniele Cusi (90, 91) , George Dedoussis (62) , Jeanette Erdmann (92) , Johan G Eriksson (18) , Denis A Evans (93) , Ulf de Faire , Martin Farrall (94) , Luigi Ferrucci (95) , Ian Ford , Lude Franke , Paul W Franks , Philippe Froguel (16, 85) , Ron T Gansevoort (96) , Christian Gieger (97) , Henrik Grönberg (5) , Vilmundur Gudnason (98, 99) , Ulf Gyllensten (100) , Per Hall , Anders Hamsten (101) , Pim van Der Harst , Caroline Hayward (100) , Markku Heliövaara , Christian Hengstenberg (102) , Andrew A Hicks , Aroon Hingorani , Albert Hofman (103) , Frank Hu , Heikki V Huikuri (104) , Kristian Hveem , Alan L James , Joanne M Jordan (105) , Antti Jula , Mika Kähönen (106) , Eero Kajantie , Sekar Kathiresan , Lambertus a L M Kiemeney (9) , Mika Kivimaki (107, 65) , Paul B Knekt , Heikki A Koistinen (108) , Jaspal S Kooner (85) , Seppo Koskinen (109) , Johanna Kuusisto (32) , Winfried Maerz , Nicholas G Martin , Markku Laakso (32) , Timo A Lakka (110) , Terho Lehtimäki (111) , Guillaume Lettre (112) , Douglas F Levinson (113) , Lars Lind , Marja-Liisa Lokki , Pekka Mäntyselkä , Mads Melbye (44) , Andres Metspalu (3, 4) , Braxton D Mitchell , Frans L Moll , Jeffrey C Murray (114) , Arthur W Musk , Markku S Nieminen , Inger Njølstad , Claes Ohlsson (115) , Albertine J Oldehinkel (116) , Ben A Oostra (103) , Lyle J Palmer , James S Pankow , Gerard Pasterkamp (117) , Nancy L Pedersen (118) , Oluf Pedersen (51, 119) , Brenda W Penninx (17) , Markus Perola (120, 121) , Annette Peters , Ozren Polašek (100) , Peter P Pramstaller (100) , Bruce M Psaty (122, 123, 124, 125, 126) , Lu Qi , Thomas Quertermous , Olli T Raitakari (127, 128) , Tuomo Rankinen , Rainer Rauramaa , Paul M Ridker (89) , John D Rioux , Fernando Rivadeneira (129) , Jerome I Rotter (130) , Igor Rudan (100) , Hester M den Ruijter , Juha Saltevo , Naveed Sattar (131) , Heribert Schunkert (92) , Peter E H Schwarz , Alan R Shuldiner , Juha Sinisalo , Harold Snieder (132, 133) , Thorkild I A Sørensen (134, 51) , Tim D Spector (9) , Jan A Staessen (135) , Bandinelli Stefania , Unnur Thorsteinsdottir (36) , Michael Stumvoll , Jean-Claude Tardif , Elena Tremoli , Jaakko Tuomilehto (136, 137, 138) , André G Uitterlinden (139, 103) , Matti Uusitupa (140) , André L M Verbeek (141) , Sita H Vermeulen , Jorma S Viikari (142) , Veronique Vitart (100) , Henry Völzke (143) , Peter Vollenweider , Gérard Waeber (144) , Mark Walker , Henri Wallaschofski , Nicholas J Wareham (145) , Hugh Watkins , Eleftheria Zeggini (28) , Aravinda Chakravarti (9) , Deborah J Clegg , L Adrienne Cupples (146) , Penny Gordon-Larsen , Cashell E Jaquish , D C Rao , Goncalo R Abecasis (47) , Themistocles L Assimes , Inês Barroso (147, 148) , Sonja I Berndt , Michael Boehnke (13) , Panos Deloukas (28) , Caroline S Fox , Leif C Groop (30) , David J Hunter , Erik Ingelsson (5) , Robert C Kaplan , Mark I Mccarthy , Karen L Mohlke (149) , Jeffrey R O'Connell (150) , David Schlessinger (47) , David P Strachan , Kari Stefansson (36) , Cornelia M van Duijn (103) , Joel N Hirschhorn (151, 152) , Cecilia M Lindgren (94, 153) , Iris M Heid (154) , Kari E North (155) , Ingrid B Borecki (1) , Zoltán Kutalik (156) , Ruth J F Loos (157)

1 Division of Statistical Genomics
2 Institut Pasteur du Cambodge
3 Estonian Genome and Medicine
4 Institute of Molecular and Cell Biology
5 MEB - Department of Medical Epidemiology and Biostatistics
6 Institute of Metabolic Science
7 Brown University
8 Center for Biological Sequence Analysis [Lyngby]
9 King‘s College London
10 Groningen Bioinformatics Centre, GBB
11 University of Queensland [Brisbane]
12 National Institut of Food Science and Technology, University of Agriculture
13 Department of Biostatistics and Center for Statistical Genetics
14 Department of neurology
15 University of Washington [Seattle]
16 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
17 Genetic Epidemiology Unit
18 Deptartment of Medical Biochemistry and Microbiology
19 Infectious diseases division, Department of internal medicine
20 Limnology
21 Department of Ecology and Evolutionary Biology
22 Core Genotyping Facility
23 Division of Cancer Epidemiology and Genetics
24 Institute of Health Sciences and Biocenter Oulu
25 DCET - NTHU - Department of Chemical Engineering Taiwan
26 University of Oxford
27 Department of Epidemiology
28 Human Genetics
29 Departments of Epidemiology and Nutrition
30 Department of Clinical Sciences
31 Genetic Epidemiology and Clinical Research Group
32 Department of Medicine
33 Department of Medical Sciences
34 Department of Educational Psychology and Counseling
35 RIKEN IMS - Laboratory for Cardiovascular Genomics and Informatics [Yokohama]
36 deCODE Genetics
37 Interuniversity Cardiology Institute Netherlands
38 Molecular Genetics Section
39 Kidney Center
40 UTHealth - The University of Texas Health Science Center at Houston
41 Texas Biomedical Research Institute [San Antonio, TX]
42 Medical Department III
43 Foie, métabolismes et cancer
44 Dept. of Epidemiology Research
45 GNS Science
46 Blackett Laboratory
47 Medstar Research Institute
48 University of Rochester [USA]
49 MRC Epidemiology Unit
50 EPI - Institute of Epidemiology [Neuherberg]
51 CBMR - Novo Nordisk Foundation Center for Basic Metabolic Research
52 Dept Biochem & Mol Biol
53 Genomic Research Laboratory, Service of Infectious Disease
54 Epidemiology
55 Unit for Molecular Epidemiology
56 Program in Translational NeuroPsychiatric Genomics,
57 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
58 HMS - Harvard Medical School [Boston]
59 RCPH - Research Centre for Prevention and Health
60 Faculty of Health and Medical Sciences
61 Faculty of Medicine, Institute of Public Health
62 Department of Nutrition-Dietetics
63 Department of Medical Statistics, Epidemiology and Medical Informatics
64 MRC National Survey of Health and Development
65 Department of Epidemiology and Public Health
66 Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
67 Research Center for Prevention and Health
68 GMM - Génétique des maladies multifactorielles
69 Cambridge Institute of Public Health
70 Chronic Disease Epidemiology and Prevention Unit
71 Queensland Institute of Medical Research
72 Medical Research Council Epidemiology Unit, Institute of Metabolic Science
73 Head of Medical Sequencing
74 MRC Unit for Lifelong Health and Ageing
75 Department of Biostatistics, University of Washington
76 Department of Chronic Disease Prevention
77 Molecular Epidemiology
78 Department of Genetics
79 Department of Medical Sciences
80 ULaval - Université Laval [Québec]
81 Interfaculty Institute for Genetics and Functional Genomics
82 Netherlands Genomics Initiative
83 Department of Internal Medicine
84 Human Genetics
85 Imperial College London
86 UNIL - Université de Lausanne = University of Lausanne
87 Carl Gustav Carus University Hospital
88 Loughborough University
89 Brigham and Women's Hospital [Boston]
90 Genomics and Bioinformatics Platform
91 Department of Medicine, Surgery, and Dentistry
92 Medizinische Klinik II
93 Department of Genomic Medicine
94 The Wellcome Trust Centre for Human Genetics [Oxford]
95 NIH - National Institutes of Health [Bethesda]
96 Department of Nephrology
97 Helmholtz Zentrum München = German Research Center for Environmental Health
98 Icelandic Heart Association, Kopavogur, Iceland.
99 Faculty of Medicine
100 Genetics and Pathology
101 Department of child and adolescent psychiatry
102 Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany
103 Erasmus MC - Erasmus University Medical Center [Rotterdam]
104 Department of Internal Medicine
105 Franz-Volhard-Centrum für Klinische Forschung, ECRC
106 Department of Clinical Physiology
107 Finnish Institute of Occupational Health of Helsinki
108 Department of Clinical Chemistry
109 Department of Oncology
110 Department of Physiology
111 Department of Clinical Chemistry
112 Department of Medicine, Montreal
113 Developmental Brain and Behaviour Unit
114 Division of Gastroenterology and Hepatology, Department of Immunology
115 Centre for Bone and Arthritis Research
116 Interdisciplinary Center for Psychiatric Epidemiology
117 Experimental Cardiology Laboratory
118 Peter MacCallum Cancer Center
119 Faculty of Health Sciences
120 FIMM - Institute for Molecular Medicine Finland [Helsinki]
121 Department of Chronic Disease Prevention
122 Department of Health Services, University of Washington
123 Group Health Research Institute, Group Health Cooperative
124 Department of Epidemiology, University of Washington
125 Department of Medicine, University of Washington
126 Cardiovascular Health Research Unit, University of Washington
127 The Research Centre of Applied and Preventive Cardiovascular Medicine
128 Department of Clinical Physiology
129 Department of Epidemiology
130 Cedars-Sinai Medical Center
131 Department of Pathological Biochemistry
132 Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen
133 Department of Pediatrics
134 Institute of Preventive Medicine
135 Department of Epidemiology
136 Department of Public Health
137 South Ostrobothnia Central Hospital
138 Department of Clinical and Preventive Medicine
139 Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
140 Institute of Public Health and Clinical Nutrition
141 Department of Epidemiology & Biostatistics
142 Department of Medicine
143 Institute for Community Medicine
144 Department of Internal Medicine
145 MRC epidemiology Unit
146 Framingham Heart Study
147 Metabolic Disease Group
148 University of Cambridge Metabolic Research Laboratories
149 Department of Genetics
150 Department of Genetics and Biotechnology
151 Divisions of Genetics and Endocrinology and Program in Genomics
152 Metabolism Initiative and Program in Medical and Population Genetics
153 Endocrinology and Metabolism
154 Department of Epidemiology and Preventive Medicine
155 Department of Epidemiology
156 Department of Medical Genetics
157 Epidemiology Unit

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.

Domains: Life Sciences [q-bio]; Genetics

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, et al.. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.. PLoS Genetics, 2015, 11 (10), pp.e1005378. ⟨10.1371/journal.pgen.1005378⟩. ⟨hal-01218025⟩