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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?

SUBMITTER: Grarup N

PROVIDER: S-EPMC6096637 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Grarup Niels N Moltke Ida I Andersen Mette K MK Bjerregaard Peter P Larsen Christina V L CVL Dahl-Petersen Inger K IK Jørsboe Emil E Tiwari Hemant K HK Hopkins Scarlett E SE Wiener Howard W HW Boyer Bert B BB Linneberg Allan A Pedersen Oluf O Jørgensen Marit E ME Albrechtsen Anders A Hansen Torben T

Diabetologia 20180620 9

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 31 ...[more]

PMID: 29926116

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Project description:Aims/hypothesisCurrent clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing.MethodsWe conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity).ResultsThirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases.Conclusions/interpretationRecessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

Dataset Information

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

Publications

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

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