The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts

Helen N Lyon, Valur Emilsson, Anke Hinney, Iris M Heid, Jessica Lasky-Su, Xiaofeng Zhu, Gudmar Thorleifsson, Steinunn Gunnarsdottir, G Bragi Walters, Unnur Thorsteinsdottir, Augustine Kong, Jeffrey Gulcher, Thuy Trang Nguyen, André Scherag, Arne Pfeufer, Thomas Meitinger, Günter Brönner, Winfried Rief, Manuel E Soto-Quiros, Lydiana Avila, Barbara Klanderman, Benjamin A Raby, Edwin K Silverman, Scott T Weiss, Nan Laird, Xiao Ding, Leif Groop, Tiinamaija Tuomi, Bo Isomaa, Kristina Bengtsson, Johannah L Butler, Richard S Cooper, Caroline S Fox, Christopher J O'Donnell, Caren Vollmert, Juan C Celedón, H Erich Wichmann, Johannes Hebebrand, Kari Stefansson, Christoph Lange, Joel N Hirschhorn, Helen N Lyon, Valur Emilsson, Anke Hinney, Iris M Heid, Jessica Lasky-Su, Xiaofeng Zhu, Gudmar Thorleifsson, Steinunn Gunnarsdottir, G Bragi Walters, Unnur Thorsteinsdottir, Augustine Kong, Jeffrey Gulcher, Thuy Trang Nguyen, André Scherag, Arne Pfeufer, Thomas Meitinger, Günter Brönner, Winfried Rief, Manuel E Soto-Quiros, Lydiana Avila, Barbara Klanderman, Benjamin A Raby, Edwin K Silverman, Scott T Weiss, Nan Laird, Xiao Ding, Leif Groop, Tiinamaija Tuomi, Bo Isomaa, Kristina Bengtsson, Johannah L Butler, Richard S Cooper, Caroline S Fox, Christopher J O'Donnell, Caren Vollmert, Juan C Celedón, H Erich Wichmann, Johannes Hebebrand, Kari Stefansson, Christoph Lange, Joel N Hirschhorn

Abstract

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.

Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

References

    1. Barsh GS, Farooqi IS, O'Rahilly S. Genetics of body-weight regulation. Nature. 2000;404:644–651.
    1. Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635–643.
    1. Allison DB, Faith MS, Nathan JS. Risch's lambda values for human obesity [comment] Int J Obes Relat Metab Disord. 1996;20:990–999.
    1. Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC, et al. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord. 1996;20:501–506.
    1. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, et al. The human obesity gene map: The 2005 update. Obesity (Silver Spring) 2006;14:529–644.
    1. Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet. 2005;37:1243–1246.
    1. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33:177–182.
    1. Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006;312:279–283.
    1. Gong Y, Lee JN, Brown MS, Goldstein JL, Ye J. Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis. Proc Natl Acad Sci U S A. 2006;103:6154–6159.
    1. Engelking LJ, Liang G, Hammer RE, Takaishi K, Kuriyama H, et al. Schoenheimer effect explained–feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J Clin Invest. 2005;115:2489–2498.
    1. Yabe D, Brown MS, Goldstein JL. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci U S A. 2002;99:12753–12758.
    1. Takaishi K, Duplomb L, Wang MY, Li J, Unger RH. Hepatic insig-1 or -2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats. Proc Natl Acad Sci U S A. 2004;101:7106–7111.
    1. Deng HW, Deng H, Liu YJ, Liu YZ, Xu FH, et al. A genomewide linkage scan for quantitative-trait loci for obesity phenotypes. Am J Hum Genet. 2002;70:1138–1151.
    1. Dina C, Meyre D, Samson C, Tichet J, Marre M, et al. Comment on “A common genetic variant is associated with adult and childhood obesity.”. Science. 2007;315:187. author reply 187.
    1. Loos RJ, Barroso I, O'Rahilly S, Wareham NJ. Comment on “A common genetic variant is associated with adult and childhood obesity.”. Science. 2007;315:187. author reply 187.
    1. Rosskopf D, Bornhorst A, Rimmbach C, Schwahn C, Kayser A, et al. Comment on “A common genetic variant is associated with adult and childhood obesity.”. Science. 2007;315:187. author reply 187.
    1. Hall DH, Rahman T, Avery PJ, Keavney B. INSIG-2 promoter polymorphism and obesity related phenotypes: Association study in 1428 members of 248 families. BMC Med Genet. 2006;7:83.
    1. Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM. PBAT: Tools for family-based association studies. Am J Hum Genet. 2004;74:367–369.
    1. Breslow NE, Day NE. Statistical methods in cancer research. Volume I - The analysis of case-control studies. IARC Sci Publ; 1980. pp. 5–338.
    1. Tarone RE. On heterogeneity tests based on efficient scores. Biometrika. 1985;72:91–95.
    1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA. 2002;288:1723–1727.
    1. Heid IM, Vollmert C, Hinney A, Doring A, Geller F, et al. Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys. J Med Genet. 2005;42:e21.
    1. Gulcher JR, Stefansson K. The Icelandic Healthcare Database and informed consent. N Engl J Med. 2000;342:1827–1830.
    1. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38:320–323.
    1. Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, et al. A common inversion under selection in Europeans. Nat Genet. 2005;37:129–137.
    1. Wichmann HE, Gieger C, Illig T. KORA-gen–resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen. 2005;67(Suppl 1):S26–S30.
    1. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol. 1979;110:281–290.
    1. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225–2229.
    1. Lyon HN, Florez JC, Bersaglieri T, Saxena R, Winckler W, et al. Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity. Diabetes. 2006;55
    1. Tang K, Fu D, Kotter S, Cotter RJ, Cantor CR, et al. Matrix-assisted laser desorption/ionization mass spectrometry of immobilized duplex DNA probes. Nucleic Acids Res. 1995;23:3126–3131.
    1. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab. 2006;91:1761–1769.
    1. Carvajal-Carmona LG, Ophoff R, Service S, Hartiala J, Molina J, et al. Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica. Hum Genet. 2003;112:534–541.
    1. Service SK, Ophoff RA, Freimer NB. The genome-wide distribution of background linkage disequilibrium in a population isolate. Hum Mol Genet. 2001;10:545–551.
    1. Hunninghake GM, Soto-Quiros ME, Avila L, Ly NP, Liang C, et al. Sensitization to Ascaris and Severity of Childhood Asthma in Costa Rica. J Allergy Clin Immunol. 2006;119:654–61.
    1. CAMP GR. The Childhood Asthma Management Program (CAMP): Design, rationale, and methods. Childhood Asthma Management Program Research Group. Control Clin Trials. 1999;20:91–120.
    1. Winckler W, Graham RR, de Bakker PI, Sun M, Almgren P, et al. Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people. Diabetes. 2005;54:886–892.
    1. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.
    1. Laird NM, Horvath S, Xu X. Implementing a unified approach to family-based tests of association. Genet Epidemiol. 2000;19(Suppl 1):S36–S42.
    1. Fisher RA. In: Statistical methods for research workers. Oa L, editor. Edinburgh: Oliver and Boyd; 1925. 239

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