Interrogating Type 2 Diabetes Genome-Wide Association Data Using a Biological Pathway-Based Approach

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 6; pp. 1463 - 1467
• Main Authors: Perry, John R.B., McCarthy, Mark I., Hattersley, Andrew T., Zeggini, Eleftheria, Weedon, Michael N., Frayling, Timothy M.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2009
• Subjects: Algorithms; Biological and medical sciences; Biology - methods; Case-Control Studies; Chromosome Mapping; Consortia; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene loci; Genetic aspects; Genetic research; Genetic Variation; Genetics; Genome-Wide Association Study; Genomes; Humans; Medical sciences; Models, Genetic; Odds Ratio; Ontology; Polymorphism, Single Nucleotide; Reference Values; Research design; Statistical analysis; Statistics; Type 2 diabetes; United States > US; Finland; Endocrinopathy; Type 2 diabetes; Metabolic diseases; Association; Genome
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db08-1378

Interrogating Type 2 Diabetes Genome-Wide Association Data Using a Biological Pathway-Based Approach John R.B. Perry 1 , Mark I. McCarthy 2 , 3 , Andrew T. Hattersley 1 , Eleftheria Zeggini 2 , the Wellcome Trust Case Control Consortium , Michael N. Weedon 1 and Timothy M. Frayling 1 1 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter, U.K.; 2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.; 3 Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford, U.K. Corresponding author: Michael Weedon, michael.weedon{at}pms.ac.uk . Abstract OBJECTIVE Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases. RESULTS After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top P adj = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas. CONCLUSIONS Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more successful for some complex traits than others, depending on the nature of the underlying disease physiology. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 7, 2008. Accepted February 18, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.