Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and...

Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. The component GRSs' weights are derived from the singular value decomposition (SVD) of the matrix of appropriately scaled genetic effects, i.e., beta coefficients, of the disease variants across a panel of the disease-related phenotypes. The SVD-based formalism also associates combinations of disease-related phenotypes with inferred disease pathways. Applied to incident type 2 diabetes (T2D) in the Women's Genome Health Study (N = 23,294), component GRSs discriminate glycemic control and lipid-based genetic risk, while revealing significant interactions between specific components and BMI or physical activity, the latter not observed with a GRS for overall T2D genetic liability. Applied to coronary artery disease (CAD) in both the WGHS and in JUPITER (N = 8,749), a randomized trial of rosuvastatin for primary prevention of CVD, component GRSs discriminate genetic risk associated with LDL-C from risk associated with reciprocal genetic effects on triglycerides and HDL-C. They also inform the pharmacogenetics of statin treatment by demonstrating that benefit from rosuvastatin is as strongly related to genetic risk from triglycerides and HDL-C as from LDL-C.