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

Thomas Winkler,Anne E. Justice,Mariaelisa Graff,Llilda Barata,Mary F. Feitosa,Su H. Chu,Jacek Czajkowski,Tõnu Esko,Tove Fall,Tuomas O. Kilpeläinen,Yingchang Lu,Reedik Mägi,Evelin Mihailov,Tune H. Pers,Sina Rüeger,Alexander Teumer,Georg Ehret,Teresa Ferreira,Nancy L. Heard‐Costa,Juha Karjalainen,Vasiliki Lagou,Anubha Mahajan,Michael D. Neinast,Inga Prokopenko,Jeannette Simino,Tanya M. Teslovich,Ritsert C. 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 E. Delgado,Ayşe Demirkan,Nicole Dueker,Niina Eklund,Guðný Eiríksdóttir,Joel Eriksson,Bjarke Feenstra,Krista Fischer,Francesca Frau,Tessel E. Galesloot,Frank Geller,Anuj Goel,Florian Kronenberg,Tanja B. Grammer,Stefan Gustafsson,Saskia Haitjema,Jouke‐Jan Hottenga,Jennifer E. Huffman,Anne 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 Ryan,Perttu Salo,Serena Sanna,Hubert Scharnagl,Jianxin Shi,Albert V. Smith,Lorraine Southam,Alena Stančáková,Valgerður Steinthórsdóttir,Rona J. Strawbridge,Yun Ju Sung,Ioanna Tachmazidou,Toshiko Tanaka,Guðmar Þorleifsson,Stella Trompet,Natalia Pervjakova,Jonathan 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 W. Cole,Francis S. Collins,E.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,J Gräßler,Harald Grallert,Niels Grarup,Yumei Gu,Linda Broer,Annelies C. Ham,Torben Hansen,Tamara B. Harris,Catharina A. Hartman,Maija Hassinen,Nicholas D. Hastie,Andrew T. Hattersley,Andrew C. Heath,Anjali K. Henders,Dena G. Hernandez,Hans L. Hillege,Oddgeir L. Holmen,Kees Hovingh,Jennie Hui,Lise Lotte Nystrup 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 Köenig,Ivana Kolčić,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. E. 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 Grazia Pilia,Anneli Pouta,Myriam Rheinberger,Rasmus Ribel‐Madsen,Marcus Richards,Kenneth Rice,Treva Rice,Carlo Rivolta,Veikko Salomaa,Alan R. Sanders,Mark A. Sarzynski,Salome Scholtens,Robert A. Scott,William R. Scott,Sylvain Sebért,Sebanti Sengupta,Bengt Sennblad,Thomas Seufferlein,Angela Silveira,P. Eline Slagboom,Jan Smit,Thomas 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,Mélanie 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. Böttinger,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 dé Fairé,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 D. Hingorani,Albert Hofman,Frank B. Hu,Heikki V. Huikuri,Kristian Hveem,Alan James,Joanne M. Jordan,Antti Jula,Mika Kähönen,Eero Kajantie,Sekar Kathiresan,Lambertus A. Kiemeney,Mika Kivimäki,Paul Knekt,Heikki A. Koistinen,Jaspal S. Kooner,Seppo Koskinen,Johanna Kuusisto,Winfried Maerz,Nicholas 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,Gérard Pasterkamp,Nancy L. Pedersen,Oluf Pedersen,Brenda W. J. H. 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 Schwarz,Alan R. Shuldiner,Juha Sinisalo,Harold Snieder,Thorkild I A Sørensen,Tim D. Spector,Jan A. Staessen,Stefania Bandinelli,Unnur Þorsteinsdóttir,Michael Stümvoll,Jean‐Claude Tardif,Elena Tremoli,Jaakko Tuomilehto,André G. Uitterlinden,Matti Uusitupa,A.L.M. Verbeek,Sita H. Vermeulen,Jorma Viikari,Véronique Vitart,Henry Völzke,Péter 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,Gonçalo R. Abecasis,Themistocles L. Assimes,Inês Barroso,Sonja I. Berndt,Michael Boehnke,Panos Deloukas,Caroline S. Fox,Leif Groop,David J. Hunter,Erik Ingelsson,Robert C. Kaplan,Mark I. McCarthy,Karen L. Mohlke,Jeffrey R. O’Connell,David Schlessinger,David P. Strachan,Kári Stefánsson,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

Anthropometry

Genome-wide association study

Biology

2015

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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“The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study” is a paper by Thomas Winkler Anne E. Justice Mariaelisa Graff Llilda Barata Mary F. Feitosa Su H. Chu Jacek Czajkowski Tõnu Esko Tove Fall Tuomas O. Kilpeläinen Yingchang Lu Reedik Mägi Evelin Mihailov Tune H. Pers Sina Rüeger Alexander Teumer Georg Ehret Teresa Ferreira Nancy L. Heard‐Costa Juha Karjalainen Vasiliki Lagou Anubha Mahajan Michael D. Neinast Inga Prokopenko Jeannette Simino Tanya M. Teslovich Ritsert C. 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 E. Delgado Ayşe Demirkan Nicole Dueker Niina Eklund Guðný Eiríksdóttir Joel Eriksson Bjarke Feenstra Krista Fischer Francesca Frau Tessel E. Galesloot Frank Geller Anuj Goel Florian Kronenberg Tanja B. Grammer Stefan Gustafsson Saskia Haitjema Jouke‐Jan Hottenga Jennifer E. Huffman Anne 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 Ryan Perttu Salo Serena Sanna Hubert Scharnagl Jianxin Shi Albert V. Smith Lorraine Southam Alena Stančáková Valgerður Steinthórsdóttir Rona J. Strawbridge Yun Ju Sung Ioanna Tachmazidou Toshiko Tanaka Guðmar Þorleifsson Stella Trompet Natalia Pervjakova Jonathan 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 W. Cole Francis S. Collins E.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 J Gräßler Harald Grallert Niels Grarup Yumei Gu Linda Broer Annelies C. Ham Torben Hansen Tamara B. Harris Catharina A. Hartman Maija Hassinen Nicholas D. Hastie Andrew T. Hattersley Andrew C. Heath Anjali K. Henders Dena G. Hernandez Hans L. Hillege Oddgeir L. Holmen Kees Hovingh Jennie Hui Lise Lotte Nystrup 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 Köenig Ivana Kolčić 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. E. 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 Grazia Pilia Anneli Pouta Myriam Rheinberger Rasmus Ribel‐Madsen Marcus Richards Kenneth Rice Treva Rice Carlo Rivolta Veikko Salomaa Alan R. Sanders Mark A. Sarzynski Salome Scholtens Robert A. Scott William R. Scott Sylvain Sebért Sebanti Sengupta Bengt Sennblad Thomas Seufferlein Angela Silveira P. Eline Slagboom Jan Smit Thomas 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 Mélanie 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. Böttinger 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 dé Fairé 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 D. Hingorani Albert Hofman Frank B. Hu Heikki V. Huikuri Kristian Hveem Alan James Joanne M. Jordan Antti Jula Mika Kähönen Eero Kajantie Sekar Kathiresan Lambertus A. Kiemeney Mika Kivimäki Paul Knekt Heikki A. Koistinen Jaspal S. Kooner Seppo Koskinen Johanna Kuusisto Winfried Maerz Nicholas 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 Gérard Pasterkamp Nancy L. Pedersen Oluf Pedersen Brenda W. J. H. 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 Schwarz Alan R. Shuldiner Juha Sinisalo Harold Snieder Thorkild I A Sørensen Tim D. Spector Jan A. Staessen Stefania Bandinelli Unnur Þorsteinsdóttir Michael Stümvoll Jean‐Claude Tardif Elena Tremoli Jaakko Tuomilehto André G. Uitterlinden Matti Uusitupa A.L.M. Verbeek Sita H. Vermeulen Jorma Viikari Véronique Vitart Henry Völzke Péter 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 Gonçalo R. Abecasis Themistocles L. Assimes Inês Barroso Sonja I. Berndt Michael Boehnke Panos Deloukas Caroline S. Fox Leif Groop David J. Hunter Erik Ingelsson Robert C. Kaplan Mark I. McCarthy Karen L. Mohlke Jeffrey R. O’Connell David Schlessinger David P. Strachan Kári Stefánsson 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 published in 2015. It has an Open Access status of “gold”. You can read and download a PDF Full Text of this paper here.