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J Neuromuscul Dis. 2019;6(2):201-211. doi: 10.3233/JND-190377.

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

Author information

1
Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
2
Department of Comparative Biosciences and Waisman Center, University of Wisconsin, Madison, WI, USA.
3
Data Management and Coordinating Center, Rare Diseases Clinical Research Network, Pediatrics Epidemiology Center, University of South Florida, Tampa, FL, USA.
4
Department of Neurology, University of Iowa, Iowa City, IA, USA.
5
Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands.
6
Department of Neurology, University of Miami, Miami, FL, USA.
7
Department of Neurology, University of Rochester, Rochester, NY, USA.
8
Department of Neurology, Stanford University, Palo Alto, CA, USA.
9
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
10
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
11
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
12
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
13
IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
14
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
15
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
16
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
17
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, UK.

Abstract

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:

We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.

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:

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:

While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.

KEYWORDS:

Charcot-marie-tooth disease; type 1a; genome-wide association study; modifier gene; single nucleotide polymorphism

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