A Multi-center Genome-wide Association Study of Cervical Dystonia

Yan V Sun^{1

2}, Chengchen Li¹, Qin Hui¹, Yunfeng Huang¹, Richard Barbano³, Ramon Rodriguez⁴, Irene A Malaty⁵, Stephen Reich⁶, Kimberly Bambarger⁶, Katie Holmes⁶, Joseph Jankovic⁷, Neepa J Patel⁸, Emmanuel Roze⁹, Marie Vidailhet⁹, Brian D Berman¹⁰, Mark S LeDoux¹¹, Alberto J Espay¹², Pinky Agarwal¹³, Sarah Pirio-Richardson¹⁴, Samuel A Frank¹⁵, William G Ondo¹⁶, Rachel Saunders-Pullman¹⁷, Sylvain Chouinard¹⁸, Stover Natividad¹⁹, Alfredo Berardelli²⁰, Alexander Y Pantelyat²¹, Allison Brashear²², Susan H Fox²³, Meike Kasten^{24

25}, Ulrike M Krämer²⁶, Miriam Neis^{26

27}, Tobias Bäumer^{24

28}, Sebastian Loens^{24

28}, Max Borsche^{24

26}, Simone Zittel²⁹, Antonia Maurer²⁹, Mathias Gelderblom²⁹, Jens Volkmann³⁰, Thorsten Odorfer³⁰, Andrea A Kühn³¹, Friederike Borngräber³¹, Inke R König³², Carlos Cruchaga³³, Adam C Cotton³⁴, Gamze Kilic-Berkmen³⁴, Alan Freeman³⁴, Stewart A Factor³⁴, Laura Scorr³⁴, J Douglas Bremner^{35

36}, Viola Vaccarino¹, Arshed A Quyyumi³⁷, Christine Klein²⁴, Joel S Perlmutter³⁸, Katja Lohmann²⁴, Hyder A Jinnah^{34

39}

Affiliations

¹ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
² Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia, USA.
³ Movement Disorders Division, University of Rochester, Rochester, New York, USA.
⁴ Neurology One, Orlando, Florida, USA.
⁵ Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA.
⁶ Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁷ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
⁸ Department of Neurology, Henry Ford Health System, Henry Ford Hospital, Detroit, Michigan, USA.
⁹ Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle; Assistance Publique - Hôpitaux de Paris, Hôpital Salpêtrière, Département de Neurologie, Paris, France.
¹⁰ Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA.
¹¹ Department of Psychology, University of Memphis, Memphis, Tennessee, USA.
¹² James J and Joan A Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA.
¹³ Booth Gardner Parkinson's Care Center, Evergreen Health, Kirkland, Washington, USA.
¹⁴ Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
¹⁵ Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹⁶ Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, Texas, USA.
¹⁷ Icahn School of Medicine at Mount Sinai, Movement Disorders, Department of Neurology, Mount Sinai Beth Israel, New York, New York, USA.
¹⁸ Unité des troubles du mouvement André-Barbeau, Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
¹⁹ Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁰ Department of Neurology and Psychiatry, Sapienza University of Rome and IRCCS Neuromed, Rome, Italy.
²¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²² Neurology, University of California, Davis, Sacramento, California, USA.
²³ University of Toronto, Edmond J Safra Program in Parkinson Disease; Movement Disorder Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
²⁴ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
²⁵ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
²⁶ Department of Neurology, University of Lübeck, Lübeck, Germany.
²⁷ Institute for Health Sciences, Department of Midwifery Science, University of Lübeck, Lübeck, Germany.
²⁸ Institute of Systemic Motor Research, University of Lübeck, Lübeck, Germany.
²⁹ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³⁰ Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
³¹ Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³² Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
³³ Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
³⁴ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁵ Atlanta VA Medical Center, Decatur, Georgia, USA.
³⁶ Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁷ Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁸ Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, Missouri, USA.
³⁹ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

PMID: 34320236
PMCID: PMC8688173
DOI: 10.1002/mds.28732

Multicenter Study

A Multi-center Genome-wide Association Study of Cervical Dystonia

Yan V Sun et al. Mov Disord. 2021 Dec.

. 2021 Dec;36(12):2795-2801.

doi: 10.1002/mds.28732. Epub 2021 Jul 28.

Authors

Affiliations

¹ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
² Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia, USA.
³ Movement Disorders Division, University of Rochester, Rochester, New York, USA.
⁴ Neurology One, Orlando, Florida, USA.
⁵ Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA.
⁶ Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁷ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
⁸ Department of Neurology, Henry Ford Health System, Henry Ford Hospital, Detroit, Michigan, USA.
⁹ Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle; Assistance Publique - Hôpitaux de Paris, Hôpital Salpêtrière, Département de Neurologie, Paris, France.
¹⁰ Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA.
¹¹ Department of Psychology, University of Memphis, Memphis, Tennessee, USA.
¹² James J and Joan A Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA.
¹³ Booth Gardner Parkinson's Care Center, Evergreen Health, Kirkland, Washington, USA.
¹⁴ Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
¹⁵ Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹⁶ Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, Texas, USA.
¹⁷ Icahn School of Medicine at Mount Sinai, Movement Disorders, Department of Neurology, Mount Sinai Beth Israel, New York, New York, USA.
¹⁸ Unité des troubles du mouvement André-Barbeau, Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
¹⁹ Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁰ Department of Neurology and Psychiatry, Sapienza University of Rome and IRCCS Neuromed, Rome, Italy.
²¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²² Neurology, University of California, Davis, Sacramento, California, USA.
²³ University of Toronto, Edmond J Safra Program in Parkinson Disease; Movement Disorder Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
²⁴ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
²⁵ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
²⁶ Department of Neurology, University of Lübeck, Lübeck, Germany.
²⁷ Institute for Health Sciences, Department of Midwifery Science, University of Lübeck, Lübeck, Germany.
²⁸ Institute of Systemic Motor Research, University of Lübeck, Lübeck, Germany.
²⁹ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³⁰ Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
³¹ Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³² Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
³³ Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
³⁴ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁵ Atlanta VA Medical Center, Decatur, Georgia, USA.
³⁶ Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁷ Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁸ Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, Missouri, USA.
³⁹ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

PMID: 34320236
PMCID: PMC8688173
DOI: 10.1002/mds.28732

Abstract

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility.

Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach.

Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal.

Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10^-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10^-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10^-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823).

Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

Keywords: cervical dystonia; genome-wide association study (GWAS); movement disorder; rare disease.

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Conflict of interest statement

Relevant conflicts of interest/financial disclosures: None

Figures

**Figure 1.**
Summary of the GWAS of cervical dystonia. Manhattan plot showed a significant locus on chromosome 3. The horizontal line represented the genome-wide significant threshold of 5×10⁻⁸. The quantile-quantile plot showed overall distribution of p-values in the GWAS.

See this image and copyright information in PMC

References

1. Albanese A, et al., Phenomenology and classification of dystonia: A consensus update. Mov Disord, 2013. 28: p. 863–873. - PMC - PubMed
1. Jinnah HA, The Dystonias. Continuum (Minneap Minn), 2019. 25(4): p. 976–1000. - PubMed
1. Defazio G, Berardelli A, and Hallett M, Do primary adult-onset focal dystonias share aetiological factors? Brain, 2007. 130(Pt 5): p. 1183–93. - PubMed
1. Jinnah HA and Sun YV, Dystonia genes and their biological pathways. Neurobiol Dis, 2019. 129: p. 159–168. - PubMed
1. Balint B and Bhatia KP, Isolated and combined dystonia syndromes - an update on new genes and their phenotypes. Eur J Neurol, 2015. 22(4): p. 610–7. - PubMed

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A Multi-center Genome-wide Association Study of Cervical Dystonia

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A Multi-center Genome-wide Association Study of Cervical Dystonia

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Conflict of interest statement

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