Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population

• Published in: Diabetologia
• Main Authors: Grarup, Niels, Moltke, Ida, Andersen, Mette K., Bjerregaard, Peter, Larsen, Christina V.L., Dahl-Petersen, Inger K., Jørsboe, Emil, Tiwari, Hemant K., Hopkins, Scarlett E., Wiener, Howard W., Boyer, Bert B., Linneberg, Allan, Pedersen, Oluf, Jørgensen, Marit E., Albrechtsen, Anders, Hansen, Torben
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2018
• Subjects: Genetic association; Genome-wide association study; Greenlanders; Inuit; ITGA1; LARGE1; Recessive genetic model; Type 2 diabetes; greenlander*; greenlandic; inuit
• Online Access: https://portal.findresearcher.sdu.dk/da/publications/d93572d6-16c8-472c-a49a-26891b05fbb6; https://doi.org/10.1007/s00125-018-4659-2; https://findresearcher.sdu.dk/ws/files/141784317/Identification_of_novel_high_impact_recessively_inherited_type_2_diabetes_risk_variants_in_the_Greenlandic_population.pdf

AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects. METHODS: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model. RESULTS: Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10 -8), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10 -7). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10 -8) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations. CONCLUSIONS/INTERPRETATION: We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations. DATA AVAILABILITY: The Greenlandic ...