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. Yum; Franco Taroni; Frank Baas; Byung Ok Choi; Davide Pareyson; Steven S. Scherer; Mary M. Reilly; Michael E. Shy; Stephan Züchner

doi:10.3233/JND-190377

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English (US)
Pages (from-to)	201-211
Number of pages	11
Journal	Journal of Neuromuscular Diseases
Volume	6
Issue number	2
DOIs	https://doi.org/10.3233/JND-190377
State	Published - 2019

Keywords

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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10.3233/JND-190377

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Tao, F., Beecham, G. W., Rebelo, A. P., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Svaren, J., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., ... Züchner, S. (2019). Modifier gene candidates in charcot-marie-tooth disease type 1A: A case-only genome-wide association study. Journal of Neuromuscular Diseases, 6(2), 201-211. https://doi.org/10.3233/JND-190377

Tao, F, Beecham, GW, Rebelo, AP, Blanton, SH, Moran, JJ, Lopez-Anido, C, Svaren, J, Abreu, L, Rizzo, D, Kirk, CA, Wu, X, Feely, S, Verhamme, C, Saporta, MA, Herrmann, DN, Day, JW, Sumner, CJ, Lloyd, TE, Li, J, Yum, SW, Taroni, F, Baas, F, Choi, BO, Pareyson, D, Scherer, SS, Reilly, MM, Shy, ME & Züchner, S 2019, 'Modifier gene candidates in charcot-marie-tooth disease type 1A: A case-only genome-wide association study', Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 201-211. https://doi.org/10.3233/JND-190377

@article{a43e7dda9ec94d01a3a07db94cf0bb57,

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

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",

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

year = "2019",

doi = "10.3233/JND-190377",

language = "English (US)",

volume = "6",

pages = "201--211",

journal = "Journal of Neuromuscular Diseases",

issn = "2214-3599",

publisher = "IOS Press BV",

number = "2",

}

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

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

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