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

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Gardner, Eugene J 
Kentistou, Katherine A 
Stankovic, Stasa 
Lockhart, Samuel 
Wheeler, Eleanor 


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.



IGF1, Mendelian randomization, UK Biobank, exome-wide association study, type 2 diabetes

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Cell Genom

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Elsevier BV
MRC (MC_UU_00006/2)
MRC (MC_UU_00006/1)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12015/2)
Wellcome Trust (214274/Z/18/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)
This work was funded by the Medical Research Council (Unit programs: MC_UU_12015/2, MC_UU_00006/2, MC_UU_12015/1, and MC_UU_00006/1). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). S.L. is supported by a Wellcome Trust Clinical PhD Fellowship (225479/Z/22/Z). S.O. is supported by a Wellcome Investigator Award (214274/Z/19/Z).