TY - JOUR
T1 - Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
AU - Grarup, Niels
AU - Moltke, Ida
AU - Andersen, Mette K.
AU - Bjerregaard, Peter
AU - Larsen, Christina V.L.
AU - Dahl-Petersen, Inger K.
AU - Jørsboe, Emil
AU - Tiwari, Hemant K.
AU - Hopkins, Scarlett E.
AU - Wiener, Howard W.
AU - Boyer, Bert B.
AU - Linneberg, Allan
AU - Pedersen, Oluf
AU - Jørgensen, Marit E.
AU - Albrechtsen, Anders
AU - Hansen, Torben
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
KW - Genetic association
KW - Genome-wide association study
KW - Greenlanders
KW - ITGA1
KW - Inuit
KW - LARGE1
KW - Recessive genetic model
KW - Type 2 diabetes
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U2 - 10.1007/s00125-018-4659-2
DO - 10.1007/s00125-018-4659-2
M3 - Article
C2 - 29926116
AN - SCOPUS:85048749142
SN - 0012-186X
VL - 61
SP - 2005
EP - 2015
JO - Diabetologia
JF - Diabetologia
IS - 9
ER -