TY - JOUR
T1 - Modifier gene candidates in charcot-marie-tooth disease type 1A: 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
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066904249&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30958311
U2 - https://doi.org/10.3233/JND-190377
DO - https://doi.org/10.3233/JND-190377
M3 - Article
C2 - 30958311
SN - 2214-3599
VL - 6
SP - 201
EP - 211
JO - Journal of Neuromuscular Diseases
JF - Journal of Neuromuscular Diseases
IS - 2
ER -