Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.
Charcot-marie-tooth disease
type 1a; genome-wide association study; modifier gene; single nucleotide polymorphism
Journal
Journal of neuromuscular diseases
ISSN: 2214-3602
Titre abrégé: J Neuromuscul Dis
Pays: Netherlands
ID NLM: 101649948
Informations de publication
Date de publication:
2019
2019
Historique:
pubmed:
9
4
2019
medline:
18
12
2019
entrez:
9
4
2019
Statut:
ppublish
Résumé
Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability. We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A. We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study. The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014). While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
Sections du résumé
BACKGROUND
BACKGROUND
Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.
OBJECTIVE
OBJECTIVE
We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.
METHODS
METHODS
We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.
RESULTS
RESULTS
The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014).
CONCLUSIONS
CONCLUSIONS
While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
Identifiants
pubmed: 30958311
pii: JND190377
doi: 10.3233/JND-190377
pmc: PMC6597974
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
201-211Subventions
Organisme : NINDS NIH HHS
ID : R01 NS094388
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS065712
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS075764
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR002737
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS043174
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090256
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS075269
Pays : United States
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