GENE PRIORITIZATION BASED ON BIOLOGICAL PLAUSIBILITY OVER GENOME WIDE ASSOCIATION STUDIES RENDERS NEW LOCI ASSOCIATED WITH TYPE 2 DIABETES.

SOOKOIAN S; FERNADEZ GIANNOTTI T; SCHUMAN, MARIANO; PIROLA CJ

Boston, USA

Conferencia; Genomics of Common Diseases; 2008

The Broad Institute of MIT and Harvard

We present an approach for expanding the selection of genes of interest as well as prioritizing SNPs associations over genome-wide association studies (GWAs) associated with genetic susceptibility to complex diseases such as type 2 diabetes. The proposed method combines both the use of open data access from the GWAs (granted by the Diabetes Genetics Initiative-DGI and the Welcome Trust Case Control Consortium-WTCCC) and the comprehensive analysis of candidate regions generated by the freely accessible ENDEAVOUR software. This model is based on both the biological plausibility of a gene-disease association and a hypothesis-driven approach. Results: The algorithm prioritized 5 genes in relation to type 2 diabetes: TACR3, ALK, CACNA1D, FOXO1A and AKT3. FOXO1A, a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic beta cells that acts downstream of the insulin signalling pathway, showed 2 SNPs significantly associated with type 2 diabetes in the WTCCC database (rs10507486 and rs7323267). The tachykinin receptor 3 of unknown function (TACR3) showed the rs1384401 significantly associated with type 2 diabetes in both databases. We estimated the p-value of each SNP in the combined dataset by Mantel-Haenszel meta-analysis, and we observed significant p-values for all SNPs except for rs897959 at AKT3. Conclusion: The proposed strategy may be used as an alternative tool for optimizing the information of the nearly 500,000 gene variants in which markers with modest significant P value for disease association are currently disregarded. Additionally, the said SNPs may be incorporated into the replication of the multistage design involved in the GWAs.