Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes

Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency < 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (GCK, GIGYF1, HNF1A) in addition to missense variants in ZEB2 (n = 31 carriers; odds ratio [OR] = 5.5 [95% confidence interval = 2.5-12.0]; p = 6.4 × 10^-7), MLXIPL (n = 245; OR = 2.3 [1.6-3.2]; p = 3.2 × 10^-7), and IGF1R (n = 394; OR = 2.4 [1.8-3.2]; p = 1.3 × 10^-10). Carriers of damaging missense variants within IGF1R were also shorter (-2.2 cm [-1.8 to -2.7]; p = 1.2 × 10^-19) and had higher circulating insulin-like growth factor-1 (IGF-1) protein levels (2.3 nmol/L [1.7-2.9]; p = 2.8 × 10^-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance was supported by Mendelian randomization analyses using common variants. These results increase understanding of the genetic architecture of T2D and highlight the growth hormone/IGF-1 axis as a potential therapeutic target.