TY - JOUR
T1 - Modifier gene candidates in charcot-marie-tooth disease type 1A
T2 - A case-only genome-wide association study
AU - Tao, Feifei
AU - Beecham, Gary W.
AU - Rebelo, Adriana P.
AU - Blanton, Susan H.
AU - Moran, John J.
AU - Lopez-Anido, Camila
AU - Svaren, John
AU - Abreu, Lisa
AU - Rizzo, Devon
AU - Kirk, Callyn A.
AU - Wu, Xingyao
AU - Feely, Shawna
AU - Verhamme, Camiel
AU - Saporta, Mario A.
AU - Herrmann, David N.
AU - Day, John W.
AU - Sumner, Charlotte J.
AU - Lloyd, Thomas E.
AU - Li, Jun
AU - Yum, Sabrina W.
AU - Taroni, Franco
AU - Baas, Frank
AU - Choi, Byung Ok
AU - Pareyson, Davide
AU - Scherer, Steven S.
AU - Reilly, Mary M.
AU - Shy, Michael E.
AU - Züchner, Stephan
N1 - Funding Information:
This work was supported by NIH (R01NS43174, U54NS065712 to M.E.S., M.M.R., S.S.S., S.Z.), NIH (R01NS075764, U54NS065712 to S.Z. and M.S., R01NS075269 to J.S. and U54HD090256), NIH (R01NS094388 to B.O.C.), the Charcot-Marie-Tooth Association, and the Muscular Dystrophy Association. M.M.R. is grateful to the Medical Research Council (MRC), MRC Centre grant (G0601943), and the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712) for their support. This research was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Publisher Copyright:
© 2019 - IOS Press and the authors. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Charcot-marie-tooth disease
KW - type 1a; genome-wide association study; modifier gene; single nucleotide polymorphism
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U2 - 10.3233/JND-190377
DO - 10.3233/JND-190377
M3 - Article
C2 - 30958311
AN - SCOPUS:85066904249
VL - 6
SP - 201
EP - 211
JO - Journal of Neuromuscular Diseases
JF - Journal of Neuromuscular Diseases
SN - 2214-3599
IS - 2
ER -