A genome-wide association study of myasthenia gravis

Alan E. Renton; Hannah A. Pliner; Carlo Provenzano; Amelia Evoli; Roberta Ricciardi; Michael A. Nalls; Giuseppe Marangi; Yevgeniya Abramzon; Sampath Arepalli; Sean Chong; Dena G. Hernandez; Janel O. Johnson; Emanuela Bartoccioni; Flavia Scuderi; Michelangelo Maestri; J. Raphael Gibbs; Edoardo Errichiello; Adriano Chiò; Gabriella Restagno; Mario Sabatelli; Mark Macek; Sonja W. Scholz; Andrea Corse; Vinay Chaudhry; Michael Benatar; Richard J. Barohn; April McVey; Mamatha Pasnoor; Mazen M. Dimachkie; Julie Rowin; John Kissel; Miriam Freimer; Henry J. Kaminski; Donald B. Sanders; Bernadette Lipscomb; Janice M. Massey; Manisha Chopra; James F. Howard; Wilma J. Koopman; Michael W. Nicolle; Robert M. Pascuzzi; Alan Pestronk; Charlie Wulf; Julaine Florence; Derrick Blackmore; Aimee Soloway; Zaeem Siddiqi; Srikanth Muppidi; Gil Wolfe; David Richman; Michelle M. Mezei; Theresa Jiwa; Joel Oger; Daniel B. Drachman; Bryan J. Traynor

doi:10.1001/jamaneurol.2014.4103

A genome-wide association study of myasthenia gravis

Alan E. Renton, Hannah A. Pliner, Carlo Provenzano, Amelia Evoli, Roberta Ricciardi, Michael A. Nalls, Giuseppe Marangi, Yevgeniya Abramzon, Sampath Arepalli, Sean Chong, Dena G. Hernandez, Janel O. Johnson, Emanuela Bartoccioni, Flavia Scuderi, Michelangelo Maestri, J. Raphael Gibbs, Edoardo Errichiello, Adriano Chiò, Gabriella Restagno, Mario SabatelliMark Macek, Sonja W. Scholz, Andrea Corse, Vinay Chaudhry, Michael Benatar, Richard J. Barohn, April McVey, Mamatha Pasnoor, Mazen M. Dimachkie, Julie Rowin, John Kissel, Miriam Freimer, Henry J. Kaminski, Donald B. Sanders, Bernadette Lipscomb, Janice M. Massey, Manisha Chopra, James F. Howard, Wilma J. Koopman, Michael W. Nicolle, Robert M. Pascuzzi, Alan Pestronk, Charlie Wulf, Julaine Florence, Derrick Blackmore, Aimee Soloway, Zaeem Siddiqi, Srikanth Muppidi, Gil Wolfe, David Richman, Michelle M. Mezei, Theresa Jiwa, Joel Oger, Daniel B. Drachman, Bryan J. Traynor

School of Medicine

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

84 Scopus citations

Abstract

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10^-8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10^-8; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10^-8; odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10-9; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10^-12; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10^-18; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10^-11; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Original language	English (US)
Pages (from-to)	396-404
Number of pages	9
Journal	JAMA Neurology
Volume	72
Issue number	4
DOIs	https://doi.org/10.1001/jamaneurol.2014.4103
State	Published - Apr 1 2015

ASJC Scopus subject areas

Clinical Neurology

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10.1001/jamaneurol.2014.4103

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Renton, A. E., Pliner, H. A., Provenzano, C., Evoli, A., Ricciardi, R., Nalls, M. A., Marangi, G., Abramzon, Y., Arepalli, S., Chong, S., Hernandez, D. G., Johnson, J. O., Bartoccioni, E., Scuderi, F., Maestri, M., Gibbs, J. R., Errichiello, E., Chiò, A., Restagno, G., ... Traynor, B. J. (2015). A genome-wide association study of myasthenia gravis. JAMA Neurology, 72(4), 396-404. https://doi.org/10.1001/jamaneurol.2014.4103

Renton, AE, Pliner, HA, Provenzano, C, Evoli, A, Ricciardi, R, Nalls, MA, Marangi, G, Abramzon, Y, Arepalli, S, Chong, S, Hernandez, DG, Johnson, JO, Bartoccioni, E, Scuderi, F, Maestri, M, Gibbs, JR, Errichiello, E, Chiò, A, Restagno, G, Sabatelli, M, Macek, M, Scholz, SW, Corse, A, Chaudhry, V, Benatar, M, Barohn, RJ, McVey, A, Pasnoor, M, Dimachkie, MM, Rowin, J, Kissel, J, Freimer, M, Kaminski, HJ, Sanders, DB, Lipscomb, B, Massey, JM, Chopra, M, Howard, JF, Koopman, WJ, Nicolle, MW, Pascuzzi, RM, Pestronk, A, Wulf, C, Florence, J, Blackmore, D, Soloway, A, Siddiqi, Z, Muppidi, S, Wolfe, G, Richman, D, Mezei, MM, Jiwa, T, Oger, J, Drachman, DB & Traynor, BJ 2015, 'A genome-wide association study of myasthenia gravis', JAMA Neurology, vol. 72, no. 4, pp. 396-404. https://doi.org/10.1001/jamaneurol.2014.4103

@article{9b738262664244deb455612b3ef180a4,

title = "A genome-wide association study of myasthenia gravis",

abstract = "IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10-8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10-8; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10-8; odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10-9; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10-12; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10-18; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10-11; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.",

author = "Renton, {Alan E.} and Pliner, {Hannah A.} and Carlo Provenzano and Amelia Evoli and Roberta Ricciardi and Nalls, {Michael A.} and Giuseppe Marangi and Yevgeniya Abramzon and Sampath Arepalli and Sean Chong and Hernandez, {Dena G.} and Johnson, {Janel O.} and Emanuela Bartoccioni and Flavia Scuderi and Michelangelo Maestri and Gibbs, {J. Raphael} and Edoardo Errichiello and Adriano Chi{\`o} and Gabriella Restagno and Mario Sabatelli and Mark Macek and Scholz, {Sonja W.} and Andrea Corse and Vinay Chaudhry and Michael Benatar and Barohn, {Richard J.} and April McVey and Mamatha Pasnoor and Dimachkie, {Mazen M.} and Julie Rowin and John Kissel and Miriam Freimer and Kaminski, {Henry J.} and Sanders, {Donald B.} and Bernadette Lipscomb and Massey, {Janice M.} and Manisha Chopra and Howard, {James F.} and Koopman, {Wilma J.} and Nicolle, {Michael W.} and Pascuzzi, {Robert M.} and Alan Pestronk and Charlie Wulf and Julaine Florence and Derrick Blackmore and Aimee Soloway and Zaeem Siddiqi and Srikanth Muppidi and Gil Wolfe and David Richman and Mezei, {Michelle M.} and Theresa Jiwa and Joel Oger and Drachman, {Daniel B.} and Traynor, {Bryan J.}",

year = "2015",

month = apr,

day = "1",

doi = "10.1001/jamaneurol.2014.4103",

language = "English (US)",

volume = "72",

pages = "396--404",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "4",

}

TY - JOUR

T1 - A genome-wide association study of myasthenia gravis

AU - Renton, Alan E.

AU - Pliner, Hannah A.

AU - Provenzano, Carlo

AU - Evoli, Amelia

AU - Ricciardi, Roberta

AU - Nalls, Michael A.

AU - Marangi, Giuseppe

AU - Abramzon, Yevgeniya

AU - Arepalli, Sampath

AU - Chong, Sean

AU - Hernandez, Dena G.

AU - Johnson, Janel O.

AU - Bartoccioni, Emanuela

AU - Scuderi, Flavia

AU - Maestri, Michelangelo

AU - Gibbs, J. Raphael

AU - Errichiello, Edoardo

AU - Chiò, Adriano

AU - Restagno, Gabriella

AU - Sabatelli, Mario

AU - Macek, Mark

AU - Scholz, Sonja W.

AU - Corse, Andrea

AU - Chaudhry, Vinay

AU - Benatar, Michael

AU - Barohn, Richard J.

AU - McVey, April

AU - Pasnoor, Mamatha

AU - Dimachkie, Mazen M.

AU - Rowin, Julie

AU - Kissel, John

AU - Freimer, Miriam

AU - Kaminski, Henry J.

AU - Sanders, Donald B.

AU - Lipscomb, Bernadette

AU - Massey, Janice M.

AU - Chopra, Manisha

AU - Howard, James F.

AU - Koopman, Wilma J.

AU - Nicolle, Michael W.

AU - Pascuzzi, Robert M.

AU - Pestronk, Alan

AU - Wulf, Charlie

AU - Florence, Julaine

AU - Blackmore, Derrick

AU - Soloway, Aimee

AU - Siddiqi, Zaeem

AU - Muppidi, Srikanth

AU - Wolfe, Gil

AU - Richman, David

AU - Mezei, Michelle M.

AU - Jiwa, Theresa

AU - Oger, Joel

AU - Drachman, Daniel B.

AU - Traynor, Bryan J.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10-8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10-8; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10-8; odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10-9; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10-12; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10-18; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10-11; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

AB - IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10-8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10-8; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10-8; odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10-9; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10-12; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10-18; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10-11; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

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DO - 10.1001/jamaneurol.2014.4103

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JO - JAMA Neurology

JF - JAMA Neurology

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ER -

A genome-wide association study of myasthenia gravis

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