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
Externally publishedYes

Fingerprint

Body Mass Index
Genotype
Single Nucleotide Polymorphism
Obesity
Genome-Wide Association Study
DNA Methylation
Sample Size
Artifacts
Meta-Analysis
Medicine
Phenotype
Weights and Measures
Population
Genes

ASJC Scopus subject areas

  • General

Cite this

Yang, J., Loos, R. J. F., Powell, J. E., Medland, S. E., Speliotes, E. K., Chasman, D. I., ... 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

FTO genotype is associated with phenotypic variability of body mass index. / 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, Ayśe; 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; Bragg-Gresham, Jennifer Lynn; 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; Carola Zillikens, M.; 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, Vol. 490, No. 7419, 11.10.2012, p. 267-273.

Research output: Contribution to journalArticle

Yang, J, Loos, RJF, Powell, JE, Medland, SE, Speliotes, EK, Chasman, DI, Rose, LM, Thorleifsson, G, Steinthorsdottir, V, Mägi, R, Waite, L, Vernon Smith, A, Yerges-Armstrong, LM, Monda, KL, Hadley, D, Mahajan, A, Li, G, Kapur, K, Vitart, V, Huffman, JE, Wang, SR, Palmer, C, Esko, T, Fischer, K, Hua Zhao, J, Demirkan, A, Isaacs, A, Feitosa, MF, Luan, JA, Heard-Costa, NL, White, C, Jackson, AU, Preuss, M, Ziegler, A, Eriksson, J, Kutalik, Z, Frau, F, Nolte, IM, Van Vliet-Ostaptchouk, JV, Hottenga, JJ, Jacobs, KB, Verweij, N, Goel, A, Medina-Gomez, C, Estrada, K, Bragg-Gresham, JL, Sanna, S, Sidore, C, Tyrer, J, Teumer, A, Prokopenko, I, Mangino, M, Lindgren, CM, Assimes, TL, Shuldiner, AR, Hui, J, Beilby, JP, McArdle, WL, Hall, P, Haritunians, T, Zgaga, L, Kolcic, I, Polasek, O, Zemunik, T, Oostra, BA, Juhani Junttila, M, Grönberg, H, Schreiber, S, Peters, A, Hicks, AA, Stephens, J, Foad, NS, Laitinen, J, Pouta, A, Kaakinen, M, Willemsen, G, Vink, JM, Wild, SH, Navis, G, Asselbergs, FW, Homuth, G, John, U, Iribarren, C, Harris, T, Launer, L, Gudnason, V, O'Connell, JR, Boerwinkle, E, Cadby, G, Palmer, LJ, James, AL, Musk, AW, Ingelsson, E, Psaty, BM, Beckmann, JS, Waeber, G, Vollenweider, P, Hayward, C, Wright, AF, Rudan, I, Groop, LC, Metspalu, A, Tee Khaw, K, Van Duijn, CM, Borecki, IB, Province, MA, Wareham, NJ, Tardif, JC, Huikuri, HV, Adrienne Cupples, L, Atwood, LD, Fox, CS, Boehnke, M, Collins, FS, Mohlke, KL, Erdmann, J, Schunkert, H, Hengstenberg, C, Stark, K, Lorentzon, M, Ohlsson, C, Cusi, D, Staessen, JA, Van Der Klauw, MM, Pramstaller, PP, Kathiresan, S, Jolley, JD, Ripatti, S, Jarvelin, MR, De Geus, EJC, Boomsma, DI, Penninx, B, Wilson, JF, Campbell, H, Chanock, SJ, Van Der Harst, P, Hamsten, A, Watkins, H, Hofman, A, Witteman, JC, Carola Zillikens, M, Uitterlinden, AG, Rivadeneira, F, Carola Zillikens, M, Kiemeney, LA, Vermeulen, SH, Abecasis, GR, Schlessinger, D, Schipf, S, Stumvoll, M, Tönjes, A, Spector, TD, North, KE, Lettre, G, McCarthy, MI, Berndt, SI, Heath, AC, Madden, PAF, Nyholt, DR, Montgomery, GW, Martin, NG, McKnight, B, Strachan, DP, Hill, WG, Snieder, H, Ridker, PM, Thorsteinsdottir, U, Stefansson, K, Frayling, TM, Hirschhorn, JN, Goddard, ME & Visscher, PM 2012, 'FTO genotype is associated with phenotypic variability of body mass index', Nature, vol. 490, no. 7419, pp. 267-273. https://doi.org/10.1038/nature11401
Yang J, Loos RJF, Powell JE, Medland SE, Speliotes EK, Chasman DI et al. FTO genotype is associated with phenotypic variability of body mass index. Nature. 2012 Oct 11;490(7419):267-273. https://doi.org/10.1038/nature11401
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, Ayśe ; 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 ; Bragg-Gresham, Jennifer Lynn ; 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 ; Carola Zillikens, M. ; 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. / FTO genotype is associated with phenotypic variability of body mass index. In: Nature. 2012 ; Vol. 490, No. 7419. pp. 267-273.
@article{dc93524a82a343a19317dfe255a9d926,
title = "FTO genotype is associated with phenotypic variability of body mass index",
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.",
author = "Jian Yang and Loos, {Ruth J F} and Powell, {Joseph E.} and Medland, {Sarah E.} and Speliotes, {Elizabeth K.} and Chasman, {Daniel I.} and Rose, {Lynda M.} and Gudmar Thorleifsson and Valgerdur Steinthorsdottir and Reedik M{\"a}gi and Lindsay Waite and {Vernon Smith}, Albert and Yerges-Armstrong, {Laura M.} and Monda, {Keri L.} and David Hadley and Anubha Mahajan and Guo Li and Karen Kapur and Veronique Vitart and Huffman, {Jennifer E.} and Wang, {Sophie R.} and Cameron Palmer and T{\~o}nu Esko and Krista Fischer and {Hua Zhao}, Jing and Ayśe Demirkan and Aaron Isaacs and Feitosa, {Mary F.} and Jian'An Luan and Heard-Costa, {Nancy L.} and Charles White and Jackson, {Anne U.} and Michael Preuss and Andreas Ziegler and Joel Eriksson and Zolt{\'a}n Kutalik and Francesca Frau and Nolte, {Ilja M.} and {Van Vliet-Ostaptchouk}, {Jana V.} and Hottenga, {Jouke Jan} and Jacobs, {Kevin B.} and Niek Verweij and Anuj Goel and Carolina Medina-Gomez and Karol Estrada and Bragg-Gresham, {Jennifer Lynn} and Serena Sanna and Carlo Sidore and Jonathan Tyrer and Alexander Teumer and Inga Prokopenko and Massimo Mangino and Lindgren, {Cecilia M.} and Assimes, {Themistocles L.} and Shuldiner, {Alan R.} and Jennie Hui and Beilby, {John P.} and McArdle, {Wendy L.} and Per Hall and Talin Haritunians and Lina Zgaga and Ivana Kolcic and Ozren Polasek and Tatijana Zemunik and Oostra, {Ben A.} and {Juhani Junttila}, M. and Henrik Gr{\"o}nberg and Stefan Schreiber and Annette Peters and Hicks, {Andrew A.} and Jonathan Stephens and Foad, {Nicola S.} and Jaana Laitinen and Anneli Pouta and Marika Kaakinen and Gonneke Willemsen and Vink, {Jacqueline M.} and Wild, {Sarah H.} and Gerjan Navis and Asselbergs, {Folkert W.} and Georg Homuth and Ulrich John and Carlos Iribarren and Tamara Harris and Lenore Launer and Vilmundur Gudnason and O'Connell, {Jeffrey R.} and Eric Boerwinkle and Gemma Cadby and Palmer, {Lyle J.} and James, {Alan L.} and Musk, {Arthur W.} and Erik Ingelsson and Psaty, {Bruce M.} and Beckmann, {Jacques S.} and Gerard Waeber and Peter Vollenweider and Caroline Hayward and Wright, {Alan F.} and Igor Rudan and Groop, {Leif C.} and Andres Metspalu and {Tee Khaw}, Kay and {Van Duijn}, {Cornelia M.} and Borecki, {Ingrid B.} and Province, {Michael A.} and Wareham, {Nicholas J.} and Tardif, {Jean Claude} and Huikuri, {Heikki V.} and {Adrienne Cupples}, L. and Atwood, {Larry D.} and Fox, {Caroline S.} and Michael Boehnke and Collins, {Francis S.} and Mohlke, {Karen L.} and Jeanette Erdmann and Heribert Schunkert and Christian Hengstenberg and Klaus Stark and Mattias Lorentzon and Claes Ohlsson and Daniele Cusi and Staessen, {Jan A.} and {Van Der Klauw}, {Melanie M.} and Pramstaller, {Peter P.} and Sekar Kathiresan and Jolley, {Jennifer D.} and Samuli Ripatti and Jarvelin, {Marjo Riitta} and {De Geus}, {Eco J C} and Boomsma, {Dorret I.} and Brenda Penninx and Wilson, {James F.} and Harry Campbell and Chanock, {Stephen J.} and {Van Der Harst}, Pim and Anders Hamsten and Hugh Watkins and Albert Hofman and Witteman, {Jacqueline C.} and {Carola Zillikens}, M. and Uitterlinden, {Andr{\'e} G.} and Fernando Rivadeneira and {Carola Zillikens}, M. and Kiemeney, {Lambertus A.} and Vermeulen, {Sita H.} and Abecasis, {Goncalo R.} and David Schlessinger and Sabine Schipf and Michael Stumvoll and Anke T{\"o}njes and Spector, {Tim D.} and North, {Kari E.} and Guillaume Lettre and McCarthy, {Mark I.} and Berndt, {Sonja I.} and Heath, {Andrew C.} and Madden, {Pamela A F} and Nyholt, {Dale R.} and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Barbara McKnight and Strachan, {David P.} and Hill, {William G.} and Harold Snieder and Ridker, {Paul M.} and Unnur Thorsteinsdottir and Kari Stefansson and Frayling, {Timothy M.} and Hirschhorn, {Joel N.} and Goddard, {Michael E.} and Visscher, {Peter M.}",
year = "2012",
month = "10",
day = "11",
doi = "10.1038/nature11401",
language = "English (US)",
volume = "490",
pages = "267--273",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7419",

}

TY - JOUR

T1 - FTO genotype is associated with phenotypic variability of body mass index

AU - Yang, Jian

AU - Loos, Ruth J F

AU - Powell, Joseph E.

AU - Medland, Sarah E.

AU - Speliotes, Elizabeth K.

AU - Chasman, Daniel I.

AU - Rose, Lynda M.

AU - Thorleifsson, Gudmar

AU - Steinthorsdottir, Valgerdur

AU - Mägi, Reedik

AU - Waite, Lindsay

AU - Vernon Smith, Albert

AU - Yerges-Armstrong, Laura M.

AU - Monda, Keri L.

AU - Hadley, David

AU - Mahajan, Anubha

AU - Li, Guo

AU - Kapur, Karen

AU - Vitart, Veronique

AU - Huffman, Jennifer E.

AU - Wang, Sophie R.

AU - Palmer, Cameron

AU - Esko, Tõnu

AU - Fischer, Krista

AU - Hua Zhao, Jing

AU - Demirkan, Ayśe

AU - Isaacs, Aaron

AU - Feitosa, Mary F.

AU - Luan, Jian'An

AU - Heard-Costa, Nancy L.

AU - White, Charles

AU - Jackson, Anne U.

AU - Preuss, Michael

AU - Ziegler, Andreas

AU - Eriksson, Joel

AU - Kutalik, Zoltán

AU - Frau, Francesca

AU - Nolte, Ilja M.

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Hottenga, Jouke Jan

AU - Jacobs, Kevin B.

AU - Verweij, Niek

AU - Goel, Anuj

AU - Medina-Gomez, Carolina

AU - Estrada, Karol

AU - Bragg-Gresham, Jennifer Lynn

AU - Sanna, Serena

AU - Sidore, Carlo

AU - Tyrer, Jonathan

AU - Teumer, Alexander

AU - Prokopenko, Inga

AU - Mangino, Massimo

AU - Lindgren, Cecilia M.

AU - Assimes, Themistocles L.

AU - Shuldiner, Alan R.

AU - Hui, Jennie

AU - Beilby, John P.

AU - McArdle, Wendy L.

AU - Hall, Per

AU - Haritunians, Talin

AU - Zgaga, Lina

AU - Kolcic, Ivana

AU - Polasek, Ozren

AU - Zemunik, Tatijana

AU - Oostra, Ben A.

AU - Juhani Junttila, M.

AU - Grönberg, Henrik

AU - Schreiber, Stefan

AU - Peters, Annette

AU - Hicks, Andrew A.

AU - Stephens, Jonathan

AU - Foad, Nicola S.

AU - Laitinen, Jaana

AU - Pouta, Anneli

AU - Kaakinen, Marika

AU - Willemsen, Gonneke

AU - Vink, Jacqueline M.

AU - Wild, Sarah H.

AU - Navis, Gerjan

AU - Asselbergs, Folkert W.

AU - Homuth, Georg

AU - John, Ulrich

AU - Iribarren, Carlos

AU - Harris, Tamara

AU - Launer, Lenore

AU - Gudnason, Vilmundur

AU - O'Connell, Jeffrey R.

AU - Boerwinkle, Eric

AU - Cadby, Gemma

AU - Palmer, Lyle J.

AU - James, Alan L.

AU - Musk, Arthur W.

AU - Ingelsson, Erik

AU - Psaty, Bruce M.

AU - Beckmann, Jacques S.

AU - Waeber, Gerard

AU - Vollenweider, Peter

AU - Hayward, Caroline

AU - Wright, Alan F.

AU - Rudan, Igor

AU - Groop, Leif C.

AU - Metspalu, Andres

AU - Tee Khaw, Kay

AU - Van Duijn, Cornelia M.

AU - Borecki, Ingrid B.

AU - Province, Michael A.

AU - Wareham, Nicholas J.

AU - Tardif, Jean Claude

AU - Huikuri, Heikki V.

AU - Adrienne Cupples, L.

AU - Atwood, Larry D.

AU - Fox, Caroline S.

AU - Boehnke, Michael

AU - Collins, Francis S.

AU - Mohlke, Karen L.

AU - Erdmann, Jeanette

AU - Schunkert, Heribert

AU - Hengstenberg, Christian

AU - Stark, Klaus

AU - Lorentzon, Mattias

AU - Ohlsson, Claes

AU - Cusi, Daniele

AU - Staessen, Jan A.

AU - Van Der Klauw, Melanie M.

AU - Pramstaller, Peter P.

AU - Kathiresan, Sekar

AU - Jolley, Jennifer D.

AU - Ripatti, Samuli

AU - Jarvelin, Marjo Riitta

AU - De Geus, Eco J C

AU - Boomsma, Dorret I.

AU - Penninx, Brenda

AU - Wilson, James F.

AU - Campbell, Harry

AU - Chanock, Stephen J.

AU - Van Der Harst, Pim

AU - Hamsten, Anders

AU - Watkins, Hugh

AU - Hofman, Albert

AU - Witteman, Jacqueline C.

AU - Carola Zillikens, M.

AU - Uitterlinden, André G.

AU - Rivadeneira, Fernando

AU - Carola Zillikens, M.

AU - Kiemeney, Lambertus A.

AU - Vermeulen, Sita H.

AU - Abecasis, Goncalo R.

AU - Schlessinger, David

AU - Schipf, Sabine

AU - Stumvoll, Michael

AU - Tönjes, Anke

AU - Spector, Tim D.

AU - North, Kari E.

AU - Lettre, Guillaume

AU - McCarthy, Mark I.

AU - Berndt, Sonja I.

AU - Heath, Andrew C.

AU - Madden, Pamela A F

AU - Nyholt, Dale R.

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - McKnight, Barbara

AU - Strachan, David P.

AU - Hill, William G.

AU - Snieder, Harold

AU - Ridker, Paul M.

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Frayling, Timothy M.

AU - Hirschhorn, Joel N.

AU - Goddard, Michael E.

AU - Visscher, Peter M.

PY - 2012/10/11

Y1 - 2012/10/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867330691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867330691&partnerID=8YFLogxK

U2 - 10.1038/nature11401

DO - 10.1038/nature11401

M3 - Article

C2 - 22982992

AN - SCOPUS:84867330691

VL - 490

SP - 267

EP - 273

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7419

ER -