FTO genotype is associated with phenotypic variability of body mass index by Yang Jian, Loos Ruth J F, Powell Joseph E, Medland Sarah E, Speliotes Elizabeth K, Chasman Daniel I, Rose Lynda M, Thorleifsson Gudmar, Steinthorsdottir Valgerdur, Mägi Reedik, Waite Lindsay, Vernon Smith Albert, Yerges-Armstrong Laura M, Monda Keri L, Hadley David, Mahajan Anubha, Li Guo, Kapur Karen, Vitart Veronique, Huffman Jennifer E, Wang Sophie R, Palmer Cameron, Esko Tõnu, Fischer Krista, Hua Zhao Jing, Demirkan Ayşe, Isaacs Aaron, Feitosa Mary F, Luan Jian'an, Heard-Costa Nancy L, White Charles, Jackson Anne U, Preuss Michael, Ziegler Andreas, Eriksson Joel, Kutalik Zoltán, Frau Francesca, Nolte Ilja M, Van Vliet-Ostaptchouk Jana V, Hottenga Jouke-Jan, Jacobs Kevin B, Verweij Niek, Goel Anuj, Medina-Gomez Carolina, Estrada Karol, Lynn Bragg-Gresham Jennifer, Sanna Serena, Sidore Carlo, Tyrer Jonathan, Teumer Alexander, Prokopenko Inga, Mangino Massimo, Lindgren Cecilia M, Assimes Themistocles L, Shuldiner Alan R, Hui Jennie, Beilby John P, McArdle Wendy L, Hall Per, Haritunians Talin, Zgaga Lina, Kolcic Ivana, Polasek Ozren, Zemunik Tatijana, Oostra Ben A, Juhani Junttila M, Grönberg Henrik, Schreiber Stefan, Peters Annette, Hicks Andrew A, Stephens Jonathan, Foad Nicola S, Laitinen Jaana, Pouta Anneli, Kaakinen Marika, Willemsen Gonneke, Vink Jacqueline M, Wild Sarah H, Navis Gerjan, Asselbergs Folkert W, Homuth Georg, John Ulrich, Iribarren Carlos, Harris Tamara, Launer Lenore, Gudnason Vilmundur, O'Connell Jeffrey R, Boerwinkle Eric, Cadby Gemma, Palmer Lyle J, James Alan L, Musk Arthur W, Ingelsson Erik, Psaty Bruce M, Beckmann Jacques S, Waeber Gerard, Vollenweider Peter, Hayward Caroline, Wright Alan F, Rudan Igor, Groop Leif C, Metspalu Andres, Tee Khaw Kay, van Duijn Cornelia M, Borecki Ingrid B, Province Michael A, Wareham Nicholas J, Tardif Jean-Claude, Huikuri Heikki V, Adrienne Cupples L, Atwood Larry D, Fox Caroline S, Boehnke Michael, Collins Francis S, Mohlke Karen L, Erdmann Jeanette, Schunkert Heribert, Hengstenberg Christian, Stark Klaus, Lorentzon Mattias, Ohlsson Claes, Cusi Daniele, Staessen Jan A, Van der Klauw Melanie M, Pramstaller Peter P, Kathiresan Sekar, Jolley Jennifer D, Ripatti Samuli, Jarvelin Marjo-Riitta, de Geus Eco J C, Boomsma Dorret I, Penninx Brenda, Wilson James F, Campbell Harry, Chanock Stephen J, van der Harst Pim, Hamsten Anders, Watkins Hugh, Hofman Albert, Witteman Jacqueline C, Carola Zillikens M, Uitterlinden André G, Rivadeneira Fernando, Kiemeney Lambertus A, Vermeulen Sita H, Abecasis Goncalo R, Schlessinger David, Schipf Sabine, Stumvoll Michael, Tönjes Anke, Spector Tim D, North Kari E, Lettre Guillaume, McCarthy Mark I, Berndt Sonja I, Heath Andrew C, Madden Pamela A F, Nyholt Dale R, Montgomery Grant W, Martin Nicholas G, McKnight Barbara, Strachan David P, Hill William G, Snieder Harold, Ridker Paul M, Thorsteinsdottir Unnur, Stefansson Kari, Frayling Timothy M, Hirschhorn Joel N, Goddard Michael E, Visscher Peter M in Nature (2012). PubMed

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.

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