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Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family

BACKGROUND: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. OBJECTIVE: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affecte...

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Autores principales: Mescheriakova, Julia Y, Verkerk, Annemieke JMH, Amin, Najaf, Uitterlinden, André G, van Duijn, Cornelia M, Hintzen, Rogier Q
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545620/
https://www.ncbi.nlm.nih.gov/pubmed/29873607
http://dx.doi.org/10.1177/1352458518777202
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author Mescheriakova, Julia Y
Verkerk, Annemieke JMH
Amin, Najaf
Uitterlinden, André G
van Duijn, Cornelia M
Hintzen, Rogier Q
author_facet Mescheriakova, Julia Y
Verkerk, Annemieke JMH
Amin, Najaf
Uitterlinden, André G
van Duijn, Cornelia M
Hintzen, Rogier Q
author_sort Mescheriakova, Julia Y
collection PubMed
description BACKGROUND: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. OBJECTIVE: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations. METHODS: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls. RESULTS: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8–2.4), p = 0.31). CONCLUSION: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk.
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spelling pubmed-65456202019-06-25 Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family Mescheriakova, Julia Y Verkerk, Annemieke JMH Amin, Najaf Uitterlinden, André G van Duijn, Cornelia M Hintzen, Rogier Q Mult Scler Original Research Papers BACKGROUND: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. OBJECTIVE: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations. METHODS: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls. RESULTS: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8–2.4), p = 0.31). CONCLUSION: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk. SAGE Publications 2018-06-06 2019-06 /pmc/articles/PMC6545620/ /pubmed/29873607 http://dx.doi.org/10.1177/1352458518777202 Text en © The Author(s), 2018 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Research Papers
Mescheriakova, Julia Y
Verkerk, Annemieke JMH
Amin, Najaf
Uitterlinden, André G
van Duijn, Cornelia M
Hintzen, Rogier Q
Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family
title Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family
title_full Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family
title_fullStr Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family
title_full_unstemmed Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family
title_short Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family
title_sort linkage analysis and whole exome sequencing identify a novel candidate gene in a dutch multiple sclerosis family
topic Original Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545620/
https://www.ncbi.nlm.nih.gov/pubmed/29873607
http://dx.doi.org/10.1177/1352458518777202
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