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

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Niels Grarup, Ida Moltke, Mette K. Andersen, Peter Bjerregaard, Christina V.L. Larsen, Inger K. Dahl-Petersen, Emil Jørsboe, Hemant K. Tiwari, Scarlett E. Hopkins, Howard W. Wiener, Bert B. Boyer, Allan Linneberg, Oluf Pedersen, Marit E. Jørgensen, Anders Albrechtsen, Torben Hansen

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 MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/) under the accession EGAS00001002641.

Original languageEnglish
JournalDiabetologia
Volume61
Issue number9
Pages (from-to)2005–2015
ISSN0012-186X
DOIs
Publication statusPublished - Sep 2018

    Research areas

  • Genetic association, Genome-wide association study, Greenlanders, Inuit, ITGA1, LARGE1, Recessive genetic model, Type 2 diabetes

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