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Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease.

ABSTRACT: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD.Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking. Cases and controls were selected from the Obstructive Lung Disease in Northern Sweden (OLIN) studies.In total, 37 genetic variants showed association with COPD (p?

SUBMITTER: Matsson H

PROVIDER: S-EPMC5106844 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease.

Matsson Hans H Söderhäll Cilla C Einarsdottir Elisabet E Lamontagne Maxime M Gudmundsson Sanna S Backman Helena H Lindberg Anne A Rönmark Eva E Kere Juha J Sin Don D Postma Dirkje S DS Bossé Yohan Y Lundbäck Bo B Klar Joakim J

BMC pulmonary medicine 20161111 1

<h4>Background</h4>Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD.<h4>Methods</h4>Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples ...[more]

PMID: 27835950

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Project description:Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; smoking is the main risk factor for COPD, but genetic factors are also relevant contributors. Genome-wide association studies (GWAS) of the lung function measures used in the diagnosis of COPD have identified a number of loci, however association signals are often broad and collectively these loci only explain a small proportion of the heritability. In order to examine the association with COPD risk of genetic variants down to low allele frequencies, to aid fine-mapping of association signals and to explain more of the missing heritability, we undertook a targeted sequencing study in 300 COPD cases and 300 smoking controls for 26 loci previously reported to be associated with lung function. We used a pooled sequencing approach, with 12 pools of 25 individuals each, enabling high depth (30x) coverage per sample to be achieved. This pooled design maximised sample size and therefore power, but led to challenges during variant-calling since sequencing error rates and minor allele frequencies for rare variants can be very similar. For this reason we employed a rigorous quality control pipeline for variant detection which included the use of 3 independent calling algorithms. In order to avoid false positive associations we also developed tests to detect variants with potential batch effects and removed them before undertaking association testing. We tested for the effects of single variants and the combined effect of rare variants within a locus. We followed up the top signals with data available (only 67% of collapsing methods signals) in 4,249 COPD cases and 11,916 smoking controls from UK Biobank. We provide suggestive evidence for the combined effect of rare variants on COPD risk in TNXB and in sliding windows within MECOM and upstream of HHIP. These findings can lead to an improved understanding of the molecular pathways involved in the development of COPD.

Dataset Information

Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease.

Publications

Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease.

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