A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.

Ivana Nedeljkovic,Diana A Van Der Plaat,Guy G Brusselle,Dandi Qiao,Lies Lahousse,Michael H Cho,Najaf Amin,Dirkje S Postma,Cleo C Van Diemen,Natalie Terzikhan,Brian D Hobbs,Judith M Vonk,Cornelia M Van Duijn,H M Boezen

doi:10.3389/fgene.2018.00133

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 [logarithm of the 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.

Highlights

Chronic obstructive pulmonary disease is a common and complex disease, and one of the leading causes of death worldwide (Lozano and Naghavi, 2012)
Using the powerful genome-wide linkage scan in a Dutch genetic isolate, we have confirmed the implication of the 15q25 region in chronic obstructive pulmonary disease (COPD) and identified regions at chromosomes 5 and 11
Within the region on chromosome 11 we identified four deleterious rare variants shared between most of the affected family members in AHNAK, PLCB3, SLC22A11 and MTL5

Summary

Introduction

Chronic obstructive pulmonary disease is a common and complex disease, and one of the leading causes of death worldwide (Lozano and Naghavi, 2012). Previous studies provided heritability estimates for COPD of 20% to even 60% (Ingebrigtsen et al, 2010; Zhou et al, 2013). Both rare variants with a large impact and common variants with a modest impact on the risk to develop COPD have been identified. Rare variants in SERPINA1 are known to contribute to COPD risk in AAT deficiency in homozygous and heterozygous carriers of the low-frequency Z allele (Foreman et al, 2017). In an exome study of severe, early-onset families, Qiao et al (2016) identified several genes with rare variants segregating in at least two pedigrees. Many initially promising findings from linkage or exome sequencing in candidate-gene studies could not be replicated in subsequent analyses (Hersh et al, 2005)

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