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A genome-wide linkage study for chronic obstructive pulmonary disease in a Dutch genetic isolate identifies novel rare candidate variants

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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.
Keywords
AIR-FLOW OBSTRUCTION, LUNG-FUNCTION, ALPHA1-ANTITRYPSIN DEFICIENCY, DRUG, TRANSPORTERS, ASSOCIATION, POPULATION, PHENOTYPES, CANCER, PEDIGREES, SMOKERS, COPD, genetic linkage analysis, genetic isolate, rare variants, chromosome 11

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Chicago
Nedeljkovic, Ivana, Natalie Terzikhan, Judith M Vonk, Diana A van der Plaat, Lies Lahousse, Cleo C van Diemen, Brian D Hobbs, et al. 2018. “A Genome-wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.” Frontiers in Genetics 9.
APA
Nedeljkovic, I., Terzikhan, N., Vonk, J. M., van der Plaat, D. A., Lahousse, L., van Diemen, C. C., Hobbs, B. D., et al. (2018). A genome-wide linkage study for chronic obstructive pulmonary disease in a Dutch genetic isolate identifies novel rare candidate variants. FRONTIERS IN GENETICS, 9.
Vancouver
1.
Nedeljkovic I, Terzikhan N, Vonk JM, van der Plaat DA, Lahousse L, van Diemen CC, et al. A genome-wide linkage study for chronic obstructive pulmonary disease in a Dutch genetic isolate identifies novel rare candidate variants. FRONTIERS IN GENETICS. 2018;9.
MLA
Nedeljkovic, Ivana et al. “A Genome-wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.” FRONTIERS IN GENETICS 9 (2018): n. pag. Print.
@article{8562645,
  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) {\textlangle}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.},
  articleno    = {133},
  author       = {Nedeljkovic, Ivana and Terzikhan, Natalie and Vonk, Judith M and van der Plaat, Diana A and Lahousse, Lies and van Diemen, Cleo C and Hobbs, Brian D and Qiao, Dandi and Cho, Michael H and Brusselle, Guy and Postma, Dirkje S and Boezen, HM and van Duijn, Cornelia M and Amin, Najaf},
  issn         = {1664-8021},
  journal      = {FRONTIERS IN GENETICS},
  language     = {eng},
  pages        = {9},
  title        = {A genome-wide linkage study for chronic obstructive pulmonary disease in a Dutch genetic isolate identifies novel rare candidate variants},
  url          = {http://dx.doi.org/10.3389/fgene.2018.00133},
  volume       = {9},
  year         = {2018},
}

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