A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
Year: 2018
Type: article
Study design: Observational Study
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 (log of odds (LOD) score=5.52), 11p15.4-11q14.1 (LOD=3.71) and 5q14.3-5q33.2 (LOD=3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.
Source: Frontiers in Genetics
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funders: European Respiratory Society, European Commission, ZonMw, Erasmus Universiteit Rotterdam, Russian Foundation for Basic Research, Erasmus Medisch Centrum, Fonds Wetenschappelijk Onderzoek, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Stichting Astma Bestrijding, Vlaamse regering, Samenwerkingsverband Noord-Nederland, Centre for Medical Systems Biology, National Heart, Lung, and Blood Institute
Awards: G1077033501, G1495020029, G1689944598, Identifying Genetic Determinants of Severe, Early-Onset COPD, G208498149, G2098337849, G2775675218, G2861369480, G2990051238, G300339986, Identifying functional variants in COPD GWAS loci, G3207356259, Network-based Methods for Understanding Genetic Determinants and Epistasis in COPD, G3540777072, G3834732120, G3839646794, G393177772, (2 of 2) Genetic Epidemiology of COPD, G4258630424, European Network for Genetic and Genomic Epidemiology, G4795516706, G5457026379, G5588026468, (1 of 2) Genetic Epidemiology of COPD, G5652732059, G5702163051, Multi-omic Subtyping of Chronic Obstructive Pulmonary Disease, G6091493096, G6759593836, G8506930532, G890705022, G8927421343
OpenAlex ID: W2800663067