年龄和性别对成人身体大小与形状的遗传关联的影响：一项大规模全基因组相互作用研究
The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
作者信息
Winkler Thomas W, Justice Anne E, Graff Mariaelisa, Barata Llilda, Feitosa Mary F, Chu Su, Czajkowski Jacek, Esko Tõnu, Fall Tove, Kilpeläinen Tuomas O, Lu Yingchang, Mägi Reedik, Mihailov Evelin, Pers Tune H, Rüeger Sina, Teumer Alexander, Ehret Georg B, Ferreira Teresa, Heard-Costa Nancy L, Karjalainen Juha, Lagou Vasiliki, Mahajan Anubha, Neinast Michael D, Prokopenko Inga, Simino Jeannette, Teslovich Tanya M, Jansen Rick, Westra Harm-Jan, White Charles C, Absher Devin, Ahluwalia Tarunveer S, Ahmad Shafqat, Albrecht Eva, Alves Alexessander Couto, Bragg-Gresham Jennifer L, de Craen Anton J M, Bis Joshua C, Bonnefond Amélie, Boucher Gabrielle, Cadby Gemma, Cheng Yu-Ching, Chiang Charleston W K, Delgado Graciela, Demirkan Ayse, Dueker Nicole, Eklund Niina, Eiriksdottir Gudny, Eriksson Joel, Feenstra Bjarke, Fischer Krista, Frau Francesca, Galesloot Tessel E, Geller Frank, Goel Anuj, Gorski Mathias, Grammer Tanja B, Gustafsson Stefan, Haitjema Saskia, Hottenga Jouke-Jan, Huffman Jennifer E, Jackson Anne U, Jacobs Kevin B, Johansson Åsa, Kaakinen Marika, Kleber Marcus E, Lahti Jari, Mateo Leach Irene, Lehne Benjamin, Liu Youfang, Lo Ken Sin, Lorentzon Mattias, Luan Jian'an, Madden Pamela A F, Mangino Massimo, McKnight Barbara, Medina-Gomez Carolina, Monda Keri L, Montasser May E, Müller Gabriele, Müller-Nurasyid Martina, Nolte Ilja M, Panoutsopoulou Kalliope, Pascoe Laura, Paternoster Lavinia, Rayner Nigel W, Renström Frida, Rizzi Federica, Rose Lynda M, Ryan Kathy A, Salo Perttu, Sanna Serena, Scharnagl Hubert, Shi Jianxin, Smith Albert Vernon, Southam Lorraine, Stančáková Alena, Steinthorsdottir Valgerdur, Strawbridge Rona J, Sung Yun Ju, Tachmazidou Ioanna, Tanaka Toshiko, Thorleifsson Gudmar, Trompet Stella, Pervjakova Natalia, Tyrer Jonathan P, Vandenput Liesbeth, van der Laan Sander W, van der Velde Nathalie, van Setten Jessica, van Vliet-Ostaptchouk Jana V, Verweij Niek, Vlachopoulou Efthymia, Waite Lindsay L, Wang Sophie R, Wang Zhaoming, Wild Sarah H, Willenborg Christina, Wilson James F, Wong Andrew, Yang Jian, Yengo Loïc, Yerges-Armstrong Laura M, Yu Lei, Zhang Weihua, Zhao Jing Hua, Andersson Ehm A, Bakker Stephan J L, Baldassarre Damiano, Banasik Karina, Barcella Matteo, Barlassina Cristina, Bellis Claire, Benaglio Paola, Blangero John, Blüher Matthias, Bonnet Fabrice, Bonnycastle Lori L, Boyd Heather A, Bruinenberg Marcel, Buchman Aron S, Campbell Harry, Chen Yii-Der Ida, Chines Peter S, Claudi-Boehm Simone, Cole John, Collins Francis S, de Geus Eco J C, de Groot Lisette C P G M, Dimitriou Maria, Duan Jubao, Enroth Stefan, Eury Elodie, Farmaki Aliki-Eleni, Forouhi Nita G, Friedrich Nele, Gejman Pablo V, Gigante Bruna, Glorioso Nicola, Go Alan S, Gottesman Omri, Gräßler Jürgen, Grallert Harald, Grarup Niels, Gu Yu-Mei, Broer Linda, Ham Annelies C, Hansen Torben, Harris Tamara B, Hartman Catharina A, Hassinen Maija, Hastie Nicholas, Hattersley Andrew T, Heath Andrew C, Henders Anjali K, Hernandez Dena, Hillege Hans, Holmen Oddgeir, Hovingh Kees G, Hui Jennie, Husemoen Lise L, Hutri-Kähönen Nina, Hysi Pirro G, Illig Thomas, De Jager Philip L, Jalilzadeh Shapour, Jørgensen Torben, Jukema J Wouter, Juonala Markus, Kanoni Stavroula, Karaleftheri Maria, Khaw Kay Tee, Kinnunen Leena, Kittner Steven J, Koenig Wolfgang, Kolcic Ivana, Kovacs Peter, Krarup Nikolaj T, Kratzer Wolfgang, Krüger Janine, Kuh Diana, Kumari Meena, Kyriakou Theodosios, Langenberg Claudia, Lannfelt Lars, Lanzani Chiara, Lotay Vaneet, Launer Lenore J, Leander Karin, Lindström Jaana, Linneberg Allan, Liu Yan-Ping, Lobbens Stéphane, Luben Robert, Lyssenko Valeriya, Männistö Satu, Magnusson Patrik K, McArdle Wendy L, Menni Cristina, Merger Sigrun, Milani Lili, Montgomery Grant W, Morris Andrew P, Narisu Narisu, Nelis Mari, Ong Ken K, Palotie Aarno, Pérusse Louis, Pichler Irene, Pilia Maria G, Pouta Anneli, Rheinberger Myriam, Ribel-Madsen Rasmus, Richards Marcus, Rice Kenneth M, Rice Treva K, Rivolta Carlo, Salomaa Veikko, Sanders Alan R, Sarzynski Mark A, Scholtens Salome, Scott Robert A, Scott William R, Sebert Sylvain, Sengupta Sebanti, Sennblad Bengt, Seufferlein Thomas, Silveira Angela, Slagboom P Eline, Smit Jan H, Sparsø Thomas H, Stirrups Kathleen, Stolk Ronald P, Stringham Heather M, Swertz Morris A, Swift Amy J, Syvänen Ann-Christine, Tan Sian-Tsung, Thorand Barbara, Tönjes Anke, Tremblay Angelo, Tsafantakis Emmanouil, van der Most Peter J, Völker Uwe, Vohl Marie-Claude, Vonk Judith M, Waldenberger Melanie, Walker Ryan W, Wennauer Roman, Widén Elisabeth, Willemsen Gonneke, Wilsgaard Tom, Wright Alan F, Zillikens M Carola, van Dijk Suzanne C, van Schoor Natasja M, Asselbergs Folkert W, de Bakker Paul I W, Beckmann Jacques S, Beilby John, Bennett David A, Bergman Richard N, Bergmann Sven, Böger Carsten A, Boehm Bernhard O, Boerwinkle Eric, Boomsma Dorret I, Bornstein Stefan R, Bottinger Erwin P, Bouchard Claude, Chambers John C, Chanock Stephen J, Chasman Daniel I, Cucca Francesco, Cusi Daniele, Dedoussis George, Erdmann Jeanette, Eriksson Johan G, Evans Denis A, de Faire Ulf, Farrall Martin, Ferrucci Luigi, Ford Ian, Franke Lude, Franks Paul W, Froguel Philippe, Gansevoort Ron T, Gieger Christian, Grönberg Henrik, Gudnason Vilmundur, Gyllensten Ulf, Hall Per, Hamsten Anders, van der Harst Pim, Hayward Caroline, Heliövaara Markku, Hengstenberg Christian, Hicks Andrew A, Hingorani Aroon, Hofman Albert, Hu Frank, Huikuri Heikki V, Hveem Kristian, James Alan L, Jordan Joanne M, Jula Antti, Kähönen Mika, Kajantie Eero, Kathiresan Sekar, Kiemeney Lambertus A L M, Kivimaki Mika, Knekt Paul B, Koistinen Heikki A, Kooner Jaspal S, Koskinen Seppo, Kuusisto Johanna, Maerz Winfried, Martin Nicholas G, Laakso Markku, Lakka Timo A, Lehtimäki Terho, Lettre Guillaume, Levinson Douglas F, Lind Lars, Lokki Marja-Liisa, Mäntyselkä Pekka, Melbye Mads, Metspalu Andres, Mitchell Braxton D, Moll Frans L, Murray Jeffrey C, Musk Arthur W, Nieminen Markku S, Njølstad Inger, Ohlsson Claes, Oldehinkel Albertine J, Oostra Ben A, Palmer Lyle J, Pankow James S, Pasterkamp Gerard, Pedersen Nancy L, Pedersen Oluf, Penninx Brenda W, Perola Markus, Peters Annette, Polašek Ozren, Pramstaller Peter P, Psaty Bruce M, Qi Lu, Quertermous Thomas, Raitakari Olli T, Rankinen Tuomo, Rauramaa Rainer, Ridker Paul M, Rioux John D, Rivadeneira Fernando, Rotter Jerome I, Rudan Igor, den Ruijter Hester M, Saltevo Juha, Sattar Naveed, Schunkert Heribert, Schwarz Peter E H, Shuldiner Alan R, Sinisalo Juha, Snieder Harold, Sørensen Thorkild I A, Spector Tim D, Staessen Jan A, Stefania Bandinelli, Thorsteinsdottir Unnur, Stumvoll Michael, Tardif Jean-Claude, Tremoli Elena, Tuomilehto Jaakko, Uitterlinden André G, Uusitupa Matti, Verbeek André L M, Vermeulen Sita H, Viikari Jorma S, Vitart Veronique, Völzke Henry, Vollenweider Peter, Waeber Gérard, Walker Mark, Wallaschofski Henri, Wareham Nicholas J, Watkins Hugh, Zeggini Eleftheria, Chakravarti Aravinda, Clegg Deborah J, Cupples L Adrienne, Gordon-Larsen Penny, Jaquish Cashell E, Rao D C, Abecasis Goncalo R, Assimes Themistocles L, Barroso Inês, Berndt Sonja I, Boehnke Michael, Deloukas Panos, Fox Caroline S, Groop Leif C, Hunter David J, Ingelsson Erik, Kaplan Robert C, McCarthy Mark I, Mohlke Karen L, O'Connell Jeffrey R, Schlessinger David, Strachan David P, Stefansson Kari, van Duijn Cornelia M, Hirschhorn Joel N, Lindgren Cecilia M, Heid Iris M, North Kari E, Borecki Ingrid B, Kutalik Zoltán, Loos Ruth J F
机构信息
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University Regensburg, Regensburg, Germany.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
出版信息
PLoS Genet. 2015 Oct 1;11(10):e1005378. doi: 10.1371/journal.pgen.1005378. eCollection 2015 Oct.
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.
全基因组关联研究（GWAS）已经鉴定出100多个影响体重指数（一种衡量体型的指标）或腰臀比（根据体重指数调整，即WHRadjBMI，一种衡量身体形状的指标）的基因变异。随着人们年龄的增长，体型和形状会发生变化，而且这些变化在男性和女性之间存在显著差异。为了系统地筛查基因变异对体重指数和WHRadjBMI的年龄和/或性别特异性影响，我们通过人体测量性状遗传研究（GIANT）联盟对114项研究（多达320485名欧洲血统个体）的全基因组芯片和/或代谢芯片数据进行了荟萃分析。每项研究在四个分层（男性≤50岁、男性>50岁、女性≤50岁、女性>50岁）中测试了多达约280万个单核苷酸多态性（SNP）与体重指数和WHRadjBMI的关联，并将汇总统计数据合并到特定分层的荟萃分析中。然后，我们筛查了显示年龄特异性效应（G×AGE）、性别特异性效应（G×SEX）或男性和女性之间不同的年龄特异性效应（G×AGE×SEX）的变异。对于体重指数，我们鉴定出15个位点（11个先前已确定其主要效应，4个新位点）显示出显著的（错误发现率<5%）年龄特异性效应，其中11个在较年轻（<50岁）人群中的效应大于老年人（≥50岁）。未发现体重指数存在性别依赖性效应。对于WHRadjBMI，我们鉴定出44个具有性别特异性效应的位点（27个先前已确定其主要效应，17个新位点），其中28个在女性中的效应大于男性，5个在男性中的效应大于女性，11个在两性之间表现出相反的效应。未发现WHRadjBMI存在年龄依赖性效应。这是第一项全基因组相互作用荟萃分析，报告了关于年龄依赖性基因对体重指数影响的确凿证据。此外，我们证实了基因对WHRadjBMI影响的性别特异性。这些结果可能为随年龄变化的体重背后的生物学机制或身体形状的性别二态性提供进一步的见解。
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