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

Type 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9x10-7) with rare, damaging variants within previously identified genes including GCK, GIGYF1, HNF1A, and TNRC6B. In addition, individuals with rare, damaging missense variants in the genes ZEB2 (N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4x10-7), MLXIPL (N=245; OR=2.3 [1.6-3.2]; p=3.2x10-7), and IGF1R (N=394; OR=2.4 [1.8-3.2]; p=1.3x10-10) have higher risk of T2D. Carriers of damaging missense variants within IGF1R were also shorter (-2.2cm [-1.8-2.7]; p=1.2x10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8x10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis.