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Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.

ABSTRACT: It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.

SUBMITTER: Lohmueller KE

PROVIDER: S-EPMC3852935 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.

Lohmueller Kirk E KE Sparsø Thomas T Li Qibin Q Andersson Ehm E Korneliussen Thorfinn T Albrechtsen Anders A Banasik Karina K Grarup Niels N Hallgrimsdottir Ingileif I Kiil Kristoffer K Kilpeläinen Tuomas O TO Krarup Nikolaj T NT Pers Tune H TH Sanchez Gaston G Hu Youna Y Degiorgio Michael M Jørgensen Torben T Sandbæk Annelli A Lauritzen Torsten T Brunak Søren S Kristiansen Karsten K Li Yingrui Y Hansen Torben T Wang Jun J Wang Jun J Nielsen Rasmus R Pedersen Oluf O

American journal of human genetics 20131127 6

It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the h ...[more]

PMID: 24290377

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Project description:ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113 genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p = 1.8 × 10-5 ), approaching study-wide significance in familial GGE (p = 3.0 × 10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9-7.8, false discovery rate [FDR]-adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3-6.7, FDR-adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3-2.5, FDR-adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9-1.9, FDR-adjusted p = .19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Dataset Information

Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.

Publications

Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.

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