Protocol detail

Comprehensive Analysis of T2D Genetic Associations

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We obtained summary statistics (association P-values and Z-scores for direction of effect or allelic effects and standard errors) for lead T2D SNPs in GWAS meta-analyses of metabolic traits in European descent populations. Summary statistics were aligned to the T2D risk allele from the combined meta-analysis. We obtained summary statistics for lead SNPs in all newly discovered and established loci for glycemic traits in non-diabetic individuals from the MAGIC Investigators^{5 (link),34}. For fasting glucose and fasting insulin, the meta-analysis comprised up to 133,010 individuals, genotyped with GWAS arrays and imputed on up to ~2.5 million SNPs, or genotyped with Metabochip. We also considered surrogate estimates of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) derived by homeostasis model assessment in up to 38,238 individuals (from GWAS meta-analysis only since these traits were not investigated in the enlarged MAGIC Metabochip study). We obtained summary statistics for lead SNPs in the newly discovered T2D loci (also including GRB14 and HMG20A) for BMI in up to 119,600 individuals from the GIANT Consortium^{15 (link)}. To eliminate potential bias in BMI allelic effect estimates at T2D susceptibility loci^{54 (link)}, we restricted our attention to meta-analysis of population-based studies not ascertained for disease status for ~2.8 million directly genotyped and/or imputed SNPs. We obtained summary statistics for the same SNPs for plasma lipid concentrations from the Global Lipids Genetics Consortium^{16 (link)}. This meta-analysis comprised ~2.6 million directly genotyped and/or imputed SNPs assessed for association to plasma concentrations of: total cholesterol (up to 100,184 individuals); LDL (up to 95,454 individuals); HDL (up to 99,900 individuals); and triglycerides (up to 96,598 individuals).
We also examined T2D association summary statistics at lead SNPs for 37 established T1D susceptibility loci. For each of these SNPs, we reported the allelic OR (aligned to the T2D risk-allele) and P-values in: (i) our Stage 1 T2D meta-analysis; and (ii) a GWAS meta-analysis of 7,514 T1D cases and 9,045 population controls from European descent populations from the Type 1 Diabetes Genetics Consortium^{35 (link)}.

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Morris A.P., Voight B.F., Teslovich T.M., Ferreira T., Segrè A.V., Steinthorsdottir V., Strawbridge R.J., Khan H., Grallert H., Mahajan A., Prokopenko I., Kang H.M., Dina C., Esko T., Fraser R.M., Kanoni S., Kumar A., Lagou V., Langenberg C., Luan J., Lindgren C.M., Müller-Nurasyid M., Pechlivanis S., Rayner N.W., Scott L.J., Wiltshire S., Yengo L., Kinnunen L., Rossin E.J., Raychaudhuri S., Johnson A.D., Dimas A.S., Loos R.J., Vedantam S., Chen H., Florez J.C., Fox C., Liu C.T., Rybin D., Couper D.J., Kao W.H., Li M., Cornelis M.C., Kraft P., Sun Q., van Dam R.M., Stringham H.M., Chines P.S., Fischer K., Fontanillas P., Holmen O.L., Hunt S.E., Jackson A.U., Kong A., Lawrence R., Meyer J., Perry J.R., Platou C.G., Potter S., Rehnberg E., Robertson N., Sivapalaratnam S., Stančáková A., Stirrups K., Thorleifsson G., Tikkanen E., Wood A.R., Almgren P., Atalay M., Benediktsson R., Bonnycastle L.L., Burtt N., Carey J., Charpentier G., Crenshaw A.T., Doney A.S., Dorkhan M., Edkins S., Emilsson V., Eury E., Forsen T., Gertow K., Gigante B., Grant G.B., Groves C.J., Guiducci C., Herder C., Hreidarsson A.B., Hui J., James A., Jonsson A., Rathmann W., Klopp N., Kravic J., Krjutškov K., Langford C., Leander K., Lindholm E., Lobbens S., Männistö S., Mirza G., Mühleisen T.W., Musk B., Parkin M., Rallidis L., Saramies J., Sennblad B., Shah S., Sigurðsson G., Silveira A., Steinbach G., Thorand B., Trakalo J., Veglia F., Wennauer R., Winckler W., Zabaneh D., Campbell H., van Duijn C., Uitterlinden89- A.G., Hofman A., Sijbrands E., Abecasis G.R., Owen K.R., Zeggini E., Trip M.D., Forouhi N.G., Syvänen A.C., Eriksson J.G., Peltonen L., Nöthen M.M., Balkau B., Palmer C.N., Lyssenko V., Tuomi T., Isomaa B., Hunter D.J., Qi L., Shuldiner A.R., Roden M., Barroso I., Wilsgaard T., Beilby J., Hovingh K., Price J.F., Wilson J.F., Rauramaa R., Lakka T.A., Lind L., Dedoussis G., Njølstad I., Pedersen N.L., Khaw K.T., Wareham N.J., Keinanen-Kiukaanniemi S.M., Saaristo T.E., Korpi-Hyövälti E., Saltevo J., Laakso M., Kuusisto J., Metspalu A., Collins F.S., Mohlke K.L., Bergman R.N., Tuomilehto J., Boehm B.O., Gieger C., Hveem K., Cauchi S., Froguel P., Baldassarre D., Tremoli E., Humphries S.E., Saleheen D., Danesh J., Ingelsson E., Ripatti S., Salomaa V., Erbel R., Jöckel K.H., Moebus S., Peters A., Illig T., de Faire U., Hamsten A., Morris A.D., Donnelly P.J., Frayling T.M., Hattersley A.T., Boerwinkle E., Melander O., Kathiresan S., Nilsson P.M., Deloukas P., Thorsteinsdottir U., Groop L.C., Stefansson K., Hu F., Pankow J.S., Dupuis J., Meigs J.B., Altshuler D., Boehnke M, & McCarthy M.I. (2012). Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature genetics, 44(9), 981-990.

Publication 2012

Allele Attention Cell function Cholesterol European Giant Glucose Grb14 Gwas Homeostasis Insulin Insulin resistance Lipid Plasma Snps Susceptibility Triglycerides Type 1 diabetes

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Protocol cited in 194 other protocols

Variable analysis

independent variables

None specified

dependent variables

Glycemic traits in non-diabetic individuals (fasting glucose, fasting insulin, HOMA-B, HOMA-IR)
Plasma lipid concentrations (total cholesterol, LDL, HDL, triglycerides)
T2D association at lead SNPs for 37 established T1D susceptibility loci

control variables

None specified

positive controls

None specified

negative controls

None specified

Annotations

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