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 for this work

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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.

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

Fingerprint

Type 2 Diabetes Mellitus
Genetic Models
Population
Chromosomes, Human, Pair 5
Linear Models

Keywords

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

Cite this

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. / Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population. In: Diabetologia. 2018 ; Vol. 61, No. 9. pp. 2005–2015.
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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 = "9",
doi = "10.1007/s00125-018-4659-2",
language = "English",
volume = "61",
pages = "2005–2015",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Heinemann",
number = "9",

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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, vol. 61, no. 9, pp. 2005–2015. https://doi.org/10.1007/s00125-018-4659-2

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

In: Diabetologia, Vol. 61, No. 9, 09.2018, p. 2005–2015.

Research output: Contribution to journalJournal articleResearchpeer-review

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

Y1 - 2018/9

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

VL - 61

SP - 2005

EP - 2015

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -