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Diabetologia. 2018 Jun 20. doi: 10.1007/s00125-018-4659-2. [Epub ahead of print]

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

Author information

1
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
2
The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
3
National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
4
Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.
5
Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
6
Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, AK, USA.
7
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
8
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
9
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
11
The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark. albrecht@binf.ku.dk.
12
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark. torben.hansen@sund.ku.dk.
13
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. torben.hansen@sund.ku.dk.

Abstract

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.

KEYWORDS:

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

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