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

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 geno...

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Autores principales: Nedeljkovic, Ivana, Terzikhan, Natalie, Vonk, Judith M., van der Plaat, Diana A., Lahousse, Lies, van Diemen, Cleo C., Hobbs, Brian D., Qiao, Dandi, Cho, Michael H., Brusselle, Guy G., Postma, Dirkje S., Boezen, H. M., van Duijn, Cornelia M., Amin, Najaf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916965/
https://www.ncbi.nlm.nih.gov/pubmed/29725345
http://dx.doi.org/10.3389/fgene.2018.00133
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author Nedeljkovic, Ivana
Terzikhan, Natalie
Vonk, Judith M.
van der Plaat, Diana A.
Lahousse, Lies
van Diemen, Cleo C.
Hobbs, Brian D.
Qiao, Dandi
Cho, Michael H.
Brusselle, Guy G.
Postma, Dirkje S.
Boezen, H. M.
van Duijn, Cornelia M.
Amin, Najaf
author_facet Nedeljkovic, Ivana
Terzikhan, Natalie
Vonk, Judith M.
van der Plaat, Diana A.
Lahousse, Lies
van Diemen, Cleo C.
Hobbs, Brian D.
Qiao, Dandi
Cho, Michael H.
Brusselle, Guy G.
Postma, Dirkje S.
Boezen, H. M.
van Duijn, Cornelia M.
Amin, Najaf
author_sort Nedeljkovic, Ivana
collection PubMed
description 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.
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spelling pubmed-59169652018-05-03 A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants Nedeljkovic, Ivana Terzikhan, Natalie Vonk, Judith M. van der Plaat, Diana A. Lahousse, Lies van Diemen, Cleo C. Hobbs, Brian D. Qiao, Dandi Cho, Michael H. Brusselle, Guy G. Postma, Dirkje S. Boezen, H. M. van Duijn, Cornelia M. Amin, Najaf Front Genet Genetics 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. Frontiers Media S.A. 2018-04-19 /pmc/articles/PMC5916965/ /pubmed/29725345 http://dx.doi.org/10.3389/fgene.2018.00133 Text en Copyright © 2018 Nedeljkovic, Terzikhan, Vonk, van der Plaat, Lahousse, van Diemen, Hobbs, Qiao, Cho, Brusselle, Postma, Boezen, van Duijn and Amin. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Nedeljkovic, Ivana
Terzikhan, Natalie
Vonk, Judith M.
van der Plaat, Diana A.
Lahousse, Lies
van Diemen, Cleo C.
Hobbs, Brian D.
Qiao, Dandi
Cho, Michael H.
Brusselle, Guy G.
Postma, Dirkje S.
Boezen, H. M.
van Duijn, Cornelia M.
Amin, Najaf
A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
title A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
title_full A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
title_fullStr A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
title_full_unstemmed A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
title_short A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants
title_sort genome-wide linkage study for chronic obstructive pulmonary disease in a dutch genetic isolate identifies novel rare candidate variants
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916965/
https://www.ncbi.nlm.nih.gov/pubmed/29725345
http://dx.doi.org/10.3389/fgene.2018.00133
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