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

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

doi:10.1007/s00125-018-4659-2

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

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^*

^*Corresponding author af dette arbejde

7 Citationer (Scopus)

75 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	61
Udgave nummer	9
Sider (fra-til)	2005–2015
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-018-4659-2
Status	Udgivet - 1 sep. 2018

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1007/s00125-018-4659-2Licens: CC BY

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic populationForlagets udgivne version, 828 KBLicens: CC BY

Citationsformater

Grarup, N., Moltke, I., Andersen, M. K., Bjerregaard, P., Larsen, C. V. L., Dahl-Petersen, I. K., Jørsboe, E., Tiwari, H. K., Hopkins, S. E., Wiener, H. W., Boyer, B. B., Linneberg, A., Pedersen, O., Jørgensen, M. E., Albrechtsen, A., & Hansen, T. (2018). Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population. Diabetologia, 61(9), 2005–2015. https://doi.org/10.1007/s00125-018-4659-2

Grarup, N , Moltke, I , Andersen, MK, Bjerregaard, P, Larsen, CVL, Dahl-Petersen, IK, Jørsboe, E, Tiwari, HK, Hopkins, SE, Wiener, HW, Boyer, BB, Linneberg, A , Pedersen, O, Jørgensen, ME, Albrechtsen, A & Hansen, T 2018, 'Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population', Diabetologia, bind 61, nr. 9, s. 2005–2015. https://doi.org/10.1007/s00125-018-4659-2

@article{9d19baa69a1c4faf874a841e03798d04,

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

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, Inuit, ITGA1, LARGE1, Recessive genetic model, Type 2 diabetes",

author = "Niels Grarup and Ida Moltke and Andersen, {Mette K.} and Peter Bjerregaard and Larsen, {Christina V.L.} and Dahl-Petersen, {Inger K.} and Emil J{\o}rsboe and Tiwari, {Hemant K.} and Hopkins, {Scarlett E.} and Wiener, {Howard W.} and Boyer, {Bert B.} and Allan Linneberg and Oluf Pedersen and J{\o}rgensen, {Marit E.} and Anders Albrechtsen and Torben Hansen",

year = "2018",

month = sep,

day = "1",

doi = "10.1007/s00125-018-4659-2",

language = "English",

volume = "61",

pages = "2005–2015",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "9",

}

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

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 - Inuit

KW - ITGA1

KW - LARGE1

KW - Recessive genetic model

KW - Type 2 diabetes

U2 - 10.1007/s00125-018-4659-2

DO - 10.1007/s00125-018-4659-2

M3 - Journal article

C2 - 29926116

AN - SCOPUS:85048749142

SN - 0012-186X

VL - 61

SP - 2005

EP - 2015

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -

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

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater