FTO genotype is associated with phenotypic variability of body mass index

Jian Yang, Ruth J.F. Loos, Joseph E. Powell, Sarah E. Medland, Elizabeth K. Speliotes, Daniel I. Chasman, Lynda M. Rose, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Reedik Mägi, Lindsay Waite, Albert Vernon Smith, Laura M. Yerges-Armstrong, Keri L. Monda, David Hadley, Anubha Mahajan, Guo Li, Karen Kapur, Veronique Vitart, Jennifer E. HuffmanSophie R. Wang, Cameron Palmer, Tõnu Esko, Krista Fischer, Jing Hua Zhao, Ayśe Demirkan, Aaron Isaacs, Mary F. Feitosa, Jian'An Luan, Nancy L. Heard-Costa, Charles White, Anne U. Jackson, Michael Preuss, Andreas Ziegler, Joel Eriksson, Zoltán Kutalik, Francesca Frau, Ilja M. Nolte, Jana V. Van Vliet-Ostaptchouk, Jouke Jan Hottenga, Kevin B. Jacobs, Niek Verweij, Anuj Goel, Carolina Medina-Gomez, Karol Estrada, Jennifer Lynn Bragg-Gresham, Serena Sanna, Carlo Sidore, Jonathan Tyrer, Alexander Teumer, Inga Prokopenko, Massimo Mangino, Cecilia M. Lindgren, Themistocles L. Assimes, Alan R. Shuldiner, Jennie Hui, John P. Beilby, Wendy L. McArdle, Per Hall, Talin Haritunians, Lina Zgaga, Ivana Kolcic, Ozren Polasek, Tatijana Zemunik, Ben A. Oostra, M. Juhani Junttila, Henrik Grönberg, Stefan Schreiber, Annette Peters, Andrew A. Hicks, Jonathan Stephens, Nicola S. Foad, Jaana Laitinen, Anneli Pouta, Marika Kaakinen, Gonneke Willemsen, Jacqueline M. Vink, Sarah H. Wild, Gerjan Navis, Folkert W. Asselbergs, Georg Homuth, Ulrich John, Carlos Iribarren, Tamara Harris, Lenore Launer, Vilmundur Gudnason, Jeffrey R. O'Connell, Eric Boerwinkle, Gemma Cadby, Lyle J. Palmer, Alan L. James, Arthur W. Musk, Erik Ingelsson, Bruce M. Psaty, Jacques S. Beckmann, Gerard Waeber, Peter Vollenweider, Caroline Hayward, Alan F. Wright, Igor Rudan, Leif C. Groop, Andres Metspalu, Kay Tee Khaw, Cornelia M. Van Duijn, Ingrid B. Borecki, Michael A. Province, Nicholas J. Wareham, Jean Claude Tardif, Heikki V. Huikuri, L. Adrienne Cupples, Larry D. Atwood, Caroline S. Fox, Michael Boehnke, Francis S. Collins, Karen L. Mohlke, Jeanette Erdmann, Heribert Schunkert, Christian Hengstenberg, Klaus Stark, Mattias Lorentzon, Claes Ohlsson, Daniele Cusi, Jan A. Staessen, Melanie M. Van Der Klauw, Peter P. Pramstaller, Sekar Kathiresan, Jennifer D. Jolley, Samuli Ripatti, Marjo Riitta Jarvelin, Eco J.C. De Geus, Dorret I. Boomsma, Brenda Penninx, James F. Wilson, Harry Campbell, Stephen J. Chanock, Pim Van Der Harst, Anders Hamsten, Hugh Watkins, Albert Hofman, Jacqueline C. Witteman, M. Carola Zillikens, André G. Uitterlinden, Fernando Rivadeneira, M. Carola Zillikens, Lambertus A. Kiemeney, Sita H. Vermeulen, Goncalo R. Abecasis, David Schlessinger, Sabine Schipf, Michael Stumvoll, Anke Tönjes, Tim D. Spector, Kari E. North, Guillaume Lettre, Mark I. McCarthy, Sonja I. Berndt, Andrew C. Heath, Pamela A.F. Madden, Dale R. Nyholt, Grant W. Montgomery, Nicholas G. Martin, Barbara McKnight, David P. Strachan, William G. Hill, Harold Snieder, Paul M. Ridker, Unnur Thorsteinsdottir, Kari Stefansson, Timothy M. Frayling, Joel N. Hirschhorn, Michael E. Goddard, Peter M. Visscher

Research output: Contribution to journalArticle

Abstract

There is evidence across several species for genetic control of phenotypic variation of complex traits, 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), 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, possibly mediated by DNA methylation. 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.

Original languageEnglish (US)
Pages (from-to)267-273
Number of pages7
JournalNature
Volume490
Issue number7419
DOIs
StatePublished - Oct 11 2012

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    Yang, J., Loos, R. J. F., Powell, J. E., Medland, S. E., Speliotes, E. K., Chasman, D. I., Rose, L. M., Thorleifsson, G., Steinthorsdottir, V., Mägi, R., Waite, L., Vernon Smith, A., Yerges-Armstrong, L. M., Monda, K. L., Hadley, D., Mahajan, A., Li, G., Kapur, K., Vitart, V., ... Visscher, P. M. (2012). FTO genotype is associated with phenotypic variability of body mass index. Nature, 490(7419), 267-273. https://doi.org/10.1038/nature11401