FTO genotype is associated with phenotypic variability of body mass index.
Yang, Jian 1,2; Loos, Ruth J. F. 3,4; Powell, Joseph E. 1,2; Medland, Sarah E. 2; Speliotes, Elizabeth K. 5,6; Chasman, Daniel I. 7,8; Rose, Lynda M. 7; Thorleifsson, Gudmar 9; Steinthorsdottir, Valgerdur 9; Magi, Reedik 10,11; Waite, Lindsay 12; Vernon Smith, Albert 13,14; Yerges-Armstrong, Laura M. 15; Monda, Keri L. 16; Hadley, David 17; Mahajan, Anubha 11; Li, Guo 18; Kapur, Karen 19,20; Vitart, Veronique 21; Huffman, Jennifer E. 21; Wang, Sophie R. 22,23,24; Palmer, Cameron 23,24; Esko, Tonu 10; Fischer, Krista 10; Hua Zhao, Jing 3; Demirkan, Ayse 25; Isaacs, Aaron 25; Feitosa, Mary F. 26; Luan, Jian'an 3; Heard-Costa, Nancy L. 27; White, Charles 27; Jackson, Anne U. 28; Preuss, Michael 29,30; Ziegler, Andreas 30; Eriksson, Joel 31; Kutalik, Zoltan 19,20; Frau, Francesca 32; Nolte, Ilja M. 33; Van Vliet-Ostaptchouk, Jana V. 34,35; Hottenga, Jouke-Jan 36; Jacobs, Kevin B. 37; Verweij, Niek 38; Goel, Anuj 11,39; Medina-Gomez, Carolina 40,41,42; Estrada, Karol 40,41,42; Lynn Bragg-Gresham, Jennifer 43; Sanna, Serena 44; Sidore, Carlo 43,45; Tyrer, Jonathan 46; Teumer, Alexander 47; Prokopenko, Inga 11,48; Mangino, Massimo 49; Lindgren, Cecilia M. 11; Assimes, Themistocles L. 50; Shuldiner, Alan R. 15,51; Hui, Jennie 52,53,54; Beilby, John P. 52,53; McArdle, Wendy L. 55; Hall, Per 56; Haritunians, Talin 57; Zgaga, Lina 58,59; Kolcic, Ivana 60; Polasek, Ozren 60; Zemunik, Tatijana 60; Oostra, Ben A. 25; Juhani Junttila, M. 61; Gronberg, Henrik 56; Schreiber, Stefan 62; Peters, Annette 63,64; Hicks, Andrew A. 65; Stephens, Jonathan 66,67; Foad, Nicola S. 66,67; Laitinen, Jaana 68; Pouta, Anneli 69,70; Kaakinen, Marika 71; Willemsen, Gonneke 36; Vink, Jacqueline M. 36; Wild, Sarah H. 58; Navis, Gerjan 72; Asselbergs, Folkert W. 73; Homuth, Georg 47; John, Ulrich 74; Iribarren, Carlos 75; Harris, Tamara 76; Launer, Lenore 76; Gudnason, Vilmundur 13,14; O'Connell, Jeffrey R. 15; Boerwinkle, Eric 77; Cadby, Gemma 78; Palmer, Lyle J. 78; James, Alan L. 79,80; Musk, Arthur W. 79,81; Ingelsson, Erik 56; Psaty, Bruce M. 82,83; Beckmann, Jacques S. 19,84; Waeber, Gerard 85; Vollenweider, Peter 85; Hayward, Caroline 21; Wright, Alan F. 21; Rudan, Igor 58,60; Groop, Leif C. 86; Metspalu, Andres 10; Tee Khaw, Kay 87; van Duijn, Cornelia M. 25; Borecki, Ingrid B. 26; Province, Michael A. 26; Wareham, Nicholas J. 3; Tardif, Jean-Claude 89,90; Huikuri, Heikki V. 61; Adrienne Cupples, L. 27,91; Atwood, Larry D. 27; Fox, Caroline S. 91; Boehnke, Michael 28; Collins, Francis S. 92; Mohlke, Karen L. 93; Erdmann, Jeanette 29,94; Schunkert, Heribert 29,94; Hengstenberg, Christian 95; Stark, Klaus 95; Lorentzon, Mattias 31; Ohlsson, Claes 31; Cusi, Daniele 32; Staessen, Jan A. 96,97; Van der Klauw, Melanie M. 34,35; Pramstaller, Peter P. 98,99,100; Kathiresan, Sekar 91,101,102,103,104; Jolley, Jennifer D. 66,67; Ripatti, Samuli 105,106,107; Jarvelin, Marjo-Riitta 69,71,108; de Geus, Eco J. C. 36; Boomsma, Dorret I. 36; Penninx, Brenda 109; Wilson, James F. 58; Campbell, Harry 58; Chanock, Stephen J. 110; van der Harst, Pim 38; Hamsten, Anders 111,112; Watkins, Hugh 11,39; Hofman, Albert 41,42; Witteman, Jacqueline C. 41,42; Uitterlinden, Andre G. 40,41,42; Rivadeneira, Fernando 40,41,42; Zillikens, M. Carola 40; Kiemeney, Lambertus A. 113; Vermeulen, Sita H. 113; Abecasis, Goncalo R. 43; Schlessinger, David 114; Schipf, Sabine 115; Stumvoll, Michael 116,117; Tonjes, Anke 116,117; Spector, Tim D. 49; North, Kari E. 118; Lettre, Guillaume 89,90; McCarthy, Mark I. 11,48,119; Berndt, Sonja I. 110; Heath, Andrew C. 120; Madden, Pamela A. F. 120; Nyholt, Dale R. 2; Montgomery, Grant W. 2; Martin, Nicholas G. 2; McKnight, Barbara 121; Strachan, David P. 17; Hill, William G. 122; Snieder, Harold 33,35; Ridker, Paul M. 7,8; Thorsteinsdottir, Unnur 9,123; Stefansson, Kari 9,123; Frayling, Timothy M. 124; Hirschhorn, Joel N. 22,23,24; Goddard, Michael E. 125,126; Visscher, Peter M. 1,2,127
[Letter]
Nature.
490(7419):267-272, October 11, 2012.
(Format: HTML, PDF)
: There is evidence across several species for genetic control of phenotypic variation of complex traits 1,2,3,4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype) 5,6,7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI 8, possibly mediated by DNA methylation 9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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