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American Journal of Epidemiology Advance Access originally published online on July 14, 2009
American Journal of Epidemiology 2009 170(5):537-545; doi:10.1093/aje/kwp145
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American Journal of Epidemiology © The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations

Georgia Salanti, Lorraine Southam, David Altshuler, Kristin Ardlie, Inês Barroso, Michael Boehnke, Marilyn C. Cornelis, Timothy M. Frayling, Harald Grallert, Niels Grarup, Leif Groop, Torben Hansen, Andrew T. Hattersley, Frank B. Hu, Kristian Hveem, Thomas Illig, Johanna Kuusisto, Markku Laakso, Claudia Langenberg, Valeriya Lyssenko, Mark I. McCarthy, Andrew Morris, Andrew D. Morris, Colin N. A. Palmer, Felicity Payne, Carl G. P. Platou, Laura J. Scott, Benjamin F. Voight, Nicholas J. Wareham, Eleftheria Zeggini and John P. A. Ioannidis

Correspondence to Dr. John P. A. Ioannidis, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece (e-mail: jioannid{at}cc.uoi.gr), or Dr. Eleftheria Zeggini, Wellcome Trust Sanger Institute, The Morgan Building, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom (eleftheria{at}sanger.ac.uk).

Received for publication January 20, 2009. Accepted for publication May 6, 2009.

For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.

Bayes theorem; diabetes mellitus, type 2; meta-analysis; models, genetic; polymorphism, genetic; population characteristics

Abbreviations: AUC, area under the receiver operating characteristic curve; OR, odds ratio; SNP, single nucleotide polymorphism


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