Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association with Insulin Clearance

Abstract

Context
Genome-wide association studies have identified >450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D).

Objective
To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply-phenotyped Mexican Americans.

Design, Setting, and Participants
457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B+L-GRS) were evaluated for association with diabetes and indexes of insulin secretion (from oral glucose tolerance test), insulin sensit...