Modifier gene candidates in charcot-marie-tooth disease type 1A: A case-only genome-wide association study

Feifei Tao, Gary W. Beecham, Adriana P. Rebelo, Susan H. Blanton, John J. Moran, Camila Lopez-Anido, John Svaren, Lisa Abreu, Devon Rizzo, Callyn A. Kirk, Xingyao Wu, Shawna Feely, Camiel Verhamme, Mario A. Saporta, David N. Herrmann, John W. Day, Charlotte J. Sumner, Thomas E. Lloyd, Jun Li, Sabrina W. YumFranco Taroni, Frank Baas, Byung Ok Choi, Davide Pareyson, Steven S. Scherer, Mary M. Reilly, Michael E. Shy, Stephan Züchner

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)201-211
Number of pages11
JournalJournal of Neuromuscular Diseases
Issue number2
StatePublished - 2019


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

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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