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

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 Padj = 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.

[1]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[2]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[3]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[4]  D. Heath,et al.  Expression Profiling and Functional Analysis of Wnt Signaling Mechanisms in Mesenchymal Stem Cells , 2004, Stem cells.

[5]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Edlund,et al.  Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. , 2005, Diabetes.

[7]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[8]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[9]  Kai Wang,et al.  Pathway-based approaches for analysis of genomewide association studies. , 2007, American journal of human genetics.

[10]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[11]  T. Frayling Genome–wide association studies provide new insights into type 2 diabetes aetiology , 2007, Nature Reviews Genetics.

[12]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[13]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[14]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[15]  M. McCarthy,et al.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes , 2008, Nature Genetics.

[16]  K. Mossman The Wellcome Trust Case Control Consortium, U.K. , 2008 .