FTO genotype is associated with phenotypic variability of body mass index

J. Yang; R.J.F. Loos; J.E. Powell; S.E. Medland; E.K. Speliotes; D.I. Chasman; L.M. Rose; G. Thorleifsson; V. Steinthorsdottir; R. Mägi; L. Waite; A. Vernon Smith; L.M. Yerges-Armstrong; K.L. Monda; D. Hadley; A. Mahajan; G. Li; K. Kapur; V. Vitart; J.E. Huffman; S.R. Wang; C. Palmer; T. Esko; K. Fischer; J. Hua Zhao; A. Demirkan; A. Isaacs; M.F. Feitosa; J. Luan; N.L. Heard-Costa; C. White; A.U. Jackson; M. Preuss; A. Ziegler; J. Eriksson; Z. Kutalik; F. Frau; I.M. Nolte; J.V. Van Vliet-Ostaptchouk; J.-J. Hottenga; K.B. Jacobs; N. Verweij; A. Goel; C. Medina-Gomez; K. Estrada; J.L. Bragg-Gresham; S. Sanna; C. Sidore; J. Tyrer; A. Teumer; I. Prokopenko; M. Mangino; C.M. Lindgren; T.L. Assimes; A.R. Shuldiner; Jennie Hui; John Beilby; W.L. Mcardle; P. Hall; T. Haritunians; L. Zgaga; I. Kolcic; O. Polasek; T. Zemunik; B.A. Oostra; M. Juhani Junttila; H. Grönberg; S. Schreiber; A. Peters; A.A. Hicks; J. Stephens; N.S. Foad; J. Laitinen; A. Pouta; M. Kaakinen; G. Willemsen; J.M. Vink; S.H. Wild; G. Navis; F.W. Asselbergs; G. Homuth; U. John; C. Iribarren; T. Harris; L. Launer; V. Gudnason; J.R. O'Connell; E. Boerwinkle; Gemma Cadby; L.J. Palmer; Alan James; Arthur Musk; E. Ingelsson; B.M. Psaty; J.S. Beckmann; G. Waeber; P. Vollenweider; C. Hayward; A.F. Wright; I. Rudan; L.C. Groop; A. Metspalu; K. Tee Khaw; C.M. Van Duijn; I.B. Borecki; M.A. Province; N.J. Wareham; J.-C. Tardif; H.V. Huikuri; L. Adrienne Cupples; L.D. Atwood; C.S. Fox; M. Boehnke; F.S. Collins; K.L. Mohlke; J. Erdmann; H. Schunkert; C. Hengstenberg; K. Stark; M. Lorentzon; C. Ohlsson; D. Cusi; J.A. Staessen; M.M. Van Der Klauw; P.P. Pramstaller; S. Kathiresan; J.D. Jolley; S. Ripatti; M.-R. Jarvelin; E.J.C. De Geus; D.I. Boomsma; B. Penninx; J.F. Wilson; H. Campbell; S.J. Chanock; P. Van Der Harst; A. Hamsten; H. Watkins; A. Hofman; J.C. Witteman; M. Carola Zillikens; A.G. Uitterlinden; F. Rivadeneira; L.A. Kiemeney; S.H. Vermeulen; G.R. Abecasis; D. Schlessinger; S. Schipf; M. Stumvoll; A. Tönjes; T.D. Spector; K.E. North; G. Lettre; M.I. Mccarthy; S.I. Berndt; A.C. Heath; P.A.F. Madden; D.R. Nyholt; G.W. Montgomery; N.G. Martin; B. Mcknight; D.P. Strachan; W.G. Hill; H. Snieder; P.M. Ridker; U. Thorsteinsdottir; K. Stefansson; T.M. Frayling; J.N. Hirschhorn; M.E. Goddard; P.M. Visscher

doi:10.1038/nature11401

FTO genotype is associated with phenotypic variability of body mass index

J. Yang, R.J.F. Loos, J.E. Powell, S.E. Medland, E.K. Speliotes, D.I. Chasman, L.M. Rose, G. Thorleifsson, V. Steinthorsdottir, R. Mägi, L. Waite, A. Vernon Smith, L.M. Yerges-Armstrong, K.L. Monda, D. Hadley, A. Mahajan, G. Li, K. Kapur, V. Vitart, J.E. HuffmanS.R. Wang, C. Palmer, T. Esko, K. Fischer, J. Hua Zhao, A. Demirkan, A. Isaacs, M.F. Feitosa, J. Luan, N.L. Heard-Costa, C. White, A.U. Jackson, M. Preuss, A. Ziegler, J. Eriksson, Z. Kutalik, F. Frau, I.M. Nolte, J.V. Van Vliet-Ostaptchouk, J.-J. Hottenga, K.B. Jacobs, N. Verweij, A. Goel, C. Medina-Gomez, K. Estrada, J.L. Bragg-Gresham, S. Sanna, C. Sidore, J. Tyrer, A. Teumer, I. Prokopenko, M. Mangino, C.M. Lindgren, T.L. Assimes, A.R. Shuldiner, Jennie Hui, John Beilby, W.L. Mcardle, P. Hall, T. Haritunians, L. Zgaga, I. Kolcic, O. Polasek, T. Zemunik, B.A. Oostra, M. Juhani Junttila, H. Grönberg, S. Schreiber, A. Peters, A.A. Hicks, J. Stephens, N.S. Foad, J. Laitinen, A. Pouta, M. Kaakinen, G. Willemsen, J.M. Vink, S.H. Wild, G. Navis, F.W. Asselbergs, G. Homuth, U. John, C. Iribarren, T. Harris, L. Launer, V. Gudnason, J.R. O'Connell, E. Boerwinkle, Gemma Cadby, L.J. Palmer, Alan James, Arthur Musk, E. Ingelsson, B.M. Psaty, J.S. Beckmann, G. Waeber, P. Vollenweider, C. Hayward, A.F. Wright, I. Rudan, L.C. Groop, A. Metspalu, K. Tee Khaw, C.M. Van Duijn, I.B. Borecki, M.A. Province, N.J. Wareham, J.-C. Tardif, H.V. Huikuri, L. Adrienne Cupples, L.D. Atwood, C.S. Fox, M. Boehnke, F.S. Collins, K.L. Mohlke, J. Erdmann, H. Schunkert, C. Hengstenberg, K. Stark, M. Lorentzon, C. Ohlsson, D. Cusi, J.A. Staessen, M.M. Van Der Klauw, P.P. Pramstaller, S. Kathiresan, J.D. Jolley, S. Ripatti, M.-R. Jarvelin, E.J.C. De Geus, D.I. Boomsma, B. Penninx, J.F. Wilson, H. Campbell, S.J. Chanock, P. Van Der Harst, A. Hamsten, H. Watkins, A. Hofman, J.C. Witteman, M. Carola Zillikens, A.G. Uitterlinden, F. Rivadeneira, L.A. Kiemeney, S.H. Vermeulen, G.R. Abecasis, D. Schlessinger, S. Schipf, M. Stumvoll, A. Tönjes, T.D. Spector, K.E. North, G. Lettre, M.I. Mccarthy, S.I. Berndt, A.C. Heath, P.A.F. Madden, D.R. Nyholt, G.W. Montgomery, N.G. Martin, B. Mcknight, D.P. Strachan, W.G. Hill, H. Snieder, P.M. Ridker, U. Thorsteinsdottir, K. Stefansson, T.M. Frayling, J.N. Hirschhorn, M.E. Goddard, P.M. Visscher

Research output: Contribution to journal › Article › peer-review

301 Citations (Scopus)

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 BMI8, possibly mediated by DNA methylation9, 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. © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Original language	English
Pages (from-to)	267-73
Journal	Nature
Volume	490
Issue number	7419
Early online date	16 Sep 2012
DOIs	https://doi.org/10.1038/nature11401
Publication status	Published - 11 Oct 2012

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10.1038/nature11401

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564953/

Cite this

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), 267-73. https://doi.org/10.1038/nature11401

@article{2bafc45503784f5eb955778e2af55a2f,

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 BMI8, possibly mediated by DNA methylation9, 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. {\textcopyright} 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.",

author = "J. Yang and R.J.F. Loos and J.E. Powell and S.E. Medland and E.K. Speliotes and D.I. Chasman and L.M. Rose and G. Thorleifsson and V. Steinthorsdottir and R. M{\"a}gi and L. Waite and {Vernon Smith}, A. and L.M. Yerges-Armstrong and K.L. Monda and D. Hadley and A. Mahajan and G. Li and K. Kapur and V. Vitart and J.E. Huffman and S.R. Wang and C. Palmer and T. Esko and K. Fischer and {Hua Zhao}, J. and A. Demirkan and A. Isaacs and M.F. Feitosa and J. Luan and N.L. Heard-Costa and C. White and A.U. Jackson and M. Preuss and A. Ziegler and J. Eriksson and Z. Kutalik and F. Frau and I.M. Nolte and {Van Vliet-Ostaptchouk}, J.V. and J.-J. Hottenga and K.B. Jacobs and N. Verweij and A. Goel and C. Medina-Gomez and K. Estrada and J.L. Bragg-Gresham and S. Sanna and C. Sidore and J. Tyrer and A. Teumer and I. Prokopenko and M. Mangino and C.M. Lindgren and T.L. Assimes and A.R. Shuldiner and Jennie Hui and John Beilby and W.L. Mcardle and P. Hall and T. Haritunians and L. Zgaga and I. Kolcic and O. Polasek and T. Zemunik and B.A. Oostra and {Juhani Junttila}, M. and H. Gr{\"o}nberg and S. Schreiber and A. Peters and A.A. Hicks and J. Stephens and N.S. Foad and J. Laitinen and A. Pouta and M. Kaakinen and G. Willemsen and J.M. Vink and S.H. Wild and G. Navis and F.W. Asselbergs and G. Homuth and U. John and C. Iribarren and T. Harris and L. Launer and V. Gudnason and J.R. O'Connell and E. Boerwinkle and Gemma Cadby and L.J. Palmer and Alan James and Arthur Musk and E. Ingelsson and B.M. Psaty and J.S. Beckmann and G. Waeber and P. Vollenweider and C. Hayward and A.F. Wright and I. Rudan and L.C. Groop and A. Metspalu and {Tee Khaw}, K. and {Van Duijn}, C.M. and I.B. Borecki and M.A. Province and N.J. Wareham and J.-C. Tardif and H.V. Huikuri and {Adrienne Cupples}, L. and L.D. Atwood and C.S. Fox and M. Boehnke and F.S. Collins and K.L. Mohlke and J. Erdmann and H. Schunkert and C. Hengstenberg and K. Stark and M. Lorentzon and C. Ohlsson and D. Cusi and J.A. Staessen and {Van Der Klauw}, M.M. and P.P. Pramstaller and S. Kathiresan and J.D. Jolley and S. Ripatti and M.-R. Jarvelin and {De Geus}, E.J.C. and D.I. Boomsma and B. Penninx and J.F. Wilson and H. Campbell and S.J. Chanock and {Van Der Harst}, P. and A. Hamsten and H. Watkins and A. Hofman and J.C. Witteman and {Carola Zillikens}, M. and A.G. Uitterlinden and F. Rivadeneira and L.A. Kiemeney and S.H. Vermeulen and G.R. Abecasis and D. Schlessinger and S. Schipf and M. Stumvoll and A. T{\"o}njes and T.D. Spector and K.E. North and G. Lettre and M.I. Mccarthy and S.I. Berndt and A.C. Heath and P.A.F. Madden and D.R. Nyholt and G.W. Montgomery and N.G. Martin and B. Mcknight and D.P. Strachan and W.G. Hill and H. Snieder and P.M. Ridker and U. Thorsteinsdottir and K. Stefansson and T.M. Frayling and J.N. Hirschhorn and M.E. Goddard and P.M. Visscher",

year = "2012",

month = oct,

day = "11",

doi = "10.1038/nature11401",

language = "English",

volume = "490",

pages = "267--73",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "7419",

}

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, J, Heard-Costa, NL, White, C, Jackson, AU, Preuss, M, Ziegler, A, Eriksson, J, Kutalik, Z, Frau, F, Nolte, IM, Van Vliet-Ostaptchouk, JV, Hottenga, J-J, 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, J, 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, A, Musk, A, 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, J-C, 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, M-R, 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, 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. 267-73. https://doi.org/10.1038/nature11401

TY - JOUR

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

AU - Yang, J.

AU - Loos, R.J.F.

AU - Powell, J.E.

AU - Medland, S.E.

AU - Speliotes, E.K.

AU - Chasman, D.I.

AU - Rose, L.M.

AU - Thorleifsson, G.

AU - Steinthorsdottir, V.

AU - Mägi, R.

AU - Waite, L.

AU - Vernon Smith, A.

AU - Yerges-Armstrong, L.M.

AU - Monda, K.L.

AU - Hadley, D.

AU - Mahajan, A.

AU - Li, G.

AU - Kapur, K.

AU - Vitart, V.

AU - Huffman, J.E.

AU - Wang, S.R.

AU - Palmer, C.

AU - Esko, T.

AU - Fischer, K.

AU - Hua Zhao, J.

AU - Demirkan, A.

AU - Isaacs, A.

AU - Feitosa, M.F.

AU - Luan, J.

AU - Heard-Costa, N.L.

AU - White, C.

AU - Jackson, A.U.

AU - Preuss, M.

AU - Ziegler, A.

AU - Eriksson, J.

AU - Kutalik, Z.

AU - Frau, F.

AU - Nolte, I.M.

AU - Van Vliet-Ostaptchouk, J.V.

AU - Hottenga, J.-J.

AU - Jacobs, K.B.

AU - Verweij, N.

AU - Goel, A.

AU - Medina-Gomez, C.

AU - Estrada, K.

AU - Bragg-Gresham, J.L.

AU - Sanna, S.

AU - Sidore, C.

AU - Tyrer, J.

AU - Teumer, A.

AU - Prokopenko, I.

AU - Mangino, M.

AU - Lindgren, C.M.

AU - Assimes, T.L.

AU - Shuldiner, A.R.

AU - Hui, Jennie

AU - Beilby, John

AU - Mcardle, W.L.

AU - Hall, P.

AU - Haritunians, T.

AU - Zgaga, L.

AU - Kolcic, I.

AU - Polasek, O.

AU - Zemunik, T.

AU - Oostra, B.A.

AU - Juhani Junttila, M.

AU - Grönberg, H.

AU - Schreiber, S.

AU - Peters, A.

AU - Hicks, A.A.

AU - Stephens, J.

AU - Foad, N.S.

AU - Laitinen, J.

AU - Pouta, A.

AU - Kaakinen, M.

AU - Willemsen, G.

AU - Vink, J.M.

AU - Wild, S.H.

AU - Navis, G.

AU - Asselbergs, F.W.

AU - Homuth, G.

AU - John, U.

AU - Iribarren, C.

AU - Harris, T.

AU - Launer, L.

AU - Gudnason, V.

AU - O'Connell, J.R.

AU - Boerwinkle, E.

AU - Cadby, Gemma

AU - Palmer, L.J.

AU - James, Alan

AU - Musk, Arthur

AU - Ingelsson, E.

AU - Psaty, B.M.

AU - Beckmann, J.S.

AU - Waeber, G.

AU - Vollenweider, P.

AU - Hayward, C.

AU - Wright, A.F.

AU - Rudan, I.

AU - Groop, L.C.

AU - Metspalu, A.

AU - Tee Khaw, K.

AU - Van Duijn, C.M.

AU - Borecki, I.B.

AU - Province, M.A.

AU - Wareham, N.J.

AU - Tardif, J.-C.

AU - Huikuri, H.V.

AU - Adrienne Cupples, L.

AU - Atwood, L.D.

AU - Fox, C.S.

AU - Boehnke, M.

AU - Collins, F.S.

AU - Mohlke, K.L.

AU - Erdmann, J.

AU - Schunkert, H.

AU - Hengstenberg, C.

AU - Stark, K.

AU - Lorentzon, M.

AU - Ohlsson, C.

AU - Cusi, D.

AU - Staessen, J.A.

AU - Van Der Klauw, M.M.

AU - Pramstaller, P.P.

AU - Kathiresan, S.

AU - Jolley, J.D.

AU - Ripatti, S.

AU - Jarvelin, M.-R.

AU - De Geus, E.J.C.

AU - Boomsma, D.I.

AU - Penninx, B.

AU - Wilson, J.F.

AU - Campbell, H.

AU - Chanock, S.J.

AU - Van Der Harst, P.

AU - Hamsten, A.

AU - Watkins, H.

AU - Hofman, A.

AU - Witteman, J.C.

AU - Carola Zillikens, M.

AU - Uitterlinden, A.G.

AU - Rivadeneira, F.

AU - Kiemeney, L.A.

AU - Vermeulen, S.H.

AU - Abecasis, G.R.

AU - Schlessinger, D.

AU - Schipf, S.

AU - Stumvoll, M.

AU - Tönjes, A.

AU - Spector, T.D.

AU - North, K.E.

AU - Lettre, G.

AU - Mccarthy, M.I.

AU - Berndt, S.I.

AU - Heath, A.C.

AU - Madden, P.A.F.

AU - Nyholt, D.R.

AU - Montgomery, G.W.

AU - Martin, N.G.

AU - Mcknight, B.

AU - Strachan, D.P.

AU - Hill, W.G.

AU - Snieder, H.

AU - Ridker, P.M.

AU - Thorsteinsdottir, U.

AU - Stefansson, K.

AU - Frayling, T.M.

AU - Hirschhorn, J.N.

AU - Goddard, M.E.

AU - Visscher, P.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 BMI8, possibly mediated by DNA methylation9, 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. © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

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 BMI8, possibly mediated by DNA methylation9, 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. © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

U2 - 10.1038/nature11401

DO - 10.1038/nature11401

M3 - Article

VL - 490

SP - 267

EP - 273

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7419

ER -

FTO genotype is associated with phenotypic variability of body mass index

Abstract

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