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://curis.ku.dk/portal/da/publications/identification-of-novel-highimpact-recessively-inherited-type-2-diabetes-risk-variants-in-the-greenlandic-population(9d19baa6-9a1c-4faf-874a-841e03798d04).html; https://doi.org/10.1007/s00125-018-4659-2; https://curis.ku.dk/ws/files/200501646/Grarup2018_Article_IdentificationOfNovelHigh_impa.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 ...