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Publication Information
Affiliation
Computational Biology Institute, The George Washington University, Ashburn, VA, USA. tmaxwell@gwu.edu.; Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Lund, Sweden.; VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA.; National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.; Center for Diabetes and Metabolic Diseases & Division of Endocrinology & Metabolism, Indiana University School of Medicine, Indianapolis, IN, USA.; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; The Biostatistics Center, The Milken Institute of Public Health, The George Washington University, Rockville, MD, USA.
Authors
Maxwell Taylor J., Franks Paul W., Kahn Steven E., Knowler William C., Mather Kieren J., Florez Jose C., Jablonski Kathleen A.
Studies
Abstract
The complex genetic architecture of type-2-diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify G×E and G×G, we screened markers for patterns indicative of interactions (relationship loci [rQTL] and variance heterogeneity loci [vQTL]). rQTL exist when the correlation between multiple traits varies by genotype and vQTL occur when the variance of a trait differs by genotype (potentially flagging G×G and G×E). In the metformin and placebo arms of the DPP (n = 1762) we screened 280,965 exomic and intergenic SNPs, for rQTL and vQTL patterns in association with year one changes from baseline in glycemia and related traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose and fasting insulin). Significant (p < 1.8 × 10−7) rQTL and vQTL generated a priori hypotheses of individual G×E tests for a SNP × metformin treatment interaction and secondarily for G×G screens. Several rQTL and vQTL identified led to 6 nominally significant (p < 0.05) metformin treatment × SNP interactions (4 for IGI, one insulin, and one glucose) and 12G×G interactions (all IGI) that exceeded experiment-wide significance (p < 4.1 × 10−9). Some loci are directly associated with incident diabetes, and others are rQTL and modify a trait’s relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). rs3197999, an ISI/insulin rQTL, is a possible gene damaging missense mutation in MST1, is associated with ulcerative colitis, sclerosing cholangitis, Crohn’s disease, BMI and coronary artery disease. This study demonstrates evidence for context-dependent effects (G×G & G×E) and the complexity of these T2D-related traits.