1130-P: A GWAS of Gene by Smoking Interaction on Type 2 Diabetes Free

Genome wide association studies (GWAS) of type 2 diabetes (T2D) have identified hundreds of genetic variants. However, the majority of these studies fail to consider the multifactorial nature and the interplay of genetic and environmental factors on disease risk, e.g., gene x environment interaction analyses. The role of smoking as a modulator in the association between genetic variants and T2D is of particular importance, since it is a modifiable risk factor for T2D. We performed a large-scale gene x smoking analysis on 345,955 individuals from 14 studies retrieved from dbGaP and UK Biobank. Phenotypic data was reviewed and harmonized prior to performing a gene by smoking GWAS for each study. A joint (main and interaction effect) framework was performed for each study. Individual study GWAS statistics were combined through meta-analysis, stratified by racial/ethnic group. The study sample includes 40,994 diabetics and 34,764 current smokers, and 324,834 of European-, 9,040 of African-, 6,125 of Hispanic-, and 5,956 of Asian-ancestry subjects. Results from the meta-analysis in the European ancestry group revealed a genome wide significant signal (p<5x10^-8) in the TCF7L2 gene (main effect, p-value 9.59x10^-33) and several genome-suggestive (p<1x10^-5) loci. We are currently expanding the analyses to include data from a total of 20 studies and 700,000 subjects. Gene by smoking interaction analysis on T2D underscores the importance of both genetic and environmental risk factors and has the potential to unveil novel variants, genes, and biological pathways that influence disease vulnerability typically missed by traditional analytic approaches.