A genome-wide linkage study for COPD in a Dutch genetic isolate

Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with common genetic variants. 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 genome-wide linkage scan. Affected-only analysis was performed using 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, Erasmus Rucphen Family (ERF) study. Potential causal variants were then selected in exome sequence data from the affected members of the families that contributed the most to the peak. The shared rare variants were further tested for association with COPD in the entire ERF study (N=657). Significant evidence for linkage was observed on chromosomes 15 (log of odds (LOD) score=5.52) and 11 (LOD=3.71). Chromosome 15 is a known COPD locus harbouring nicotinic receptors. In the chromosome 11 locus we identified several rare (minor allele frequency (MAF)<0.02) predicted pathogenic variants. They were shared among the affected family members and associated with COPD in the entire ERF study (P<0.03). The identified variants localize to genes including solute carrier family (SLC22A11), involved in the amino acids metabolism and ion transport; metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism; neuroblast differentiation-associated protein (AHNAK), reported by GWAS of blood biomarkers in COPD and Phospholipase C Beta 3 (PLCB3), reported by GWAS of asthma. In conclusion, we have identified novel rare variants in plausible genes related to COPD, which will be further explored by replication using exome sequencing in a large independent population-based cohort