Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

Björn Hergen Laabs; Katja Lohmann; Eva Juliane Vollstedt; Tobias Reinberger; Lisa Marie Nuxoll; Gamze Kilic-Berkmen; Joel S. Perlmutter; Sebastian Loens; Carlos Cruchaga; Andre Franke; Valerija Dobricic; Frauke Hinrichs; Anne Grözinger; Eckart Altenmüller; Steven Bellows; Sylvia Boesch; Susan B. Bressman; Kevin R. Duque; Alberto J. Espay; Andreas Ferbert; Jeanne S. Feuerstein; Samuel Frank; Thomas Gasser; Bernhard Haslinger; Robert Jech; Frank Kaiser; Christoph Kamm; Katja Kollewe; Andrea A. Kühn; Mark S. LeDoux; Ebba Lohmann; Abhimanyu Mahajan; Alexander Münchau; Trisha Multhaupt-Buell; Alexander Pantelyat; Sarah E. Pirio Richardson; Deborah Raymond; Stephen G. Reich; Rachel Saunders Pullman; Barbara Schormair; Nutan Sharma; Azadeh Hamzehei Sichani; Kristina Simonyan; Jens Volkmann; Aparna Wagle Shukla; Juliane Winkelmann; Laura J. Wright; Michael Zech; Kirsten E. Zeuner; Simone Zittel; Meike Kasten; Yan V. Sun; Tobias Bäumer; Norbert Brüggemann; Laurie J. Ozelius; Hyder A. Jinnah; Christine Klein; Inke R. König

doi:10.1002/mds.29968

Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

Björn Hergen Laabs, Katja Lohmann, Eva Juliane Vollstedt, Tobias Reinberger, Lisa Marie Nuxoll, Gamze Kilic-Berkmen, Joel S. Perlmutter, Sebastian Loens, Carlos Cruchaga, Andre Franke, Valerija Dobricic, Frauke Hinrichs, Anne Grözinger, Eckart Altenmüller, Steven Bellows, Sylvia Boesch, Susan B. Bressman, Kevin R. Duque, Alberto J. Espay, Andreas FerbertJeanne S. Feuerstein, Samuel Frank, Thomas Gasser, Bernhard Haslinger, Robert Jech, Frank Kaiser, Christoph Kamm, Katja Kollewe, Andrea A. Kühn, Mark S. LeDoux, Ebba Lohmann, Abhimanyu Mahajan, Alexander Münchau, Trisha Multhaupt-Buell, Alexander Pantelyat, Sarah E. Pirio Richardson, Deborah Raymond, Stephen G. Reich, Rachel Saunders Pullman, Barbara Schormair, Nutan Sharma, Azadeh Hamzehei Sichani, Kristina Simonyan, Jens Volkmann, Aparna Wagle Shukla, Juliane Winkelmann, Laura J. Wright, Michael Zech, Kirsten E. Zeuner, Simone Zittel, Meike Kasten, Yan V. Sun, Tobias Bäumer, Norbert Brüggemann, Laurie J. Ozelius, Hyder A. Jinnah, Christine Klein, Inke R. König

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Abstract

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. Conclusions: Moderate single-nucleotide polymorphism–based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis.

Original language	English
Pages (from-to)	2110-2116
Number of pages	7
Journal	Movement Disorders
Volume	39
Issue number	11
DOIs	https://doi.org/10.1002/mds.29968
State	Published - Nov 2024

Keywords

GWAS
age at onset
case–control
clinical score
isolated dystonia

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Laabs, B. H., Lohmann, K., Vollstedt, E. J., Reinberger, T., Nuxoll, L. M., Kilic-Berkmen, G., Perlmutter, J. S., Loens, S., Cruchaga, C., Franke, A., Dobricic, V., Hinrichs, F., Grözinger, A., Altenmüller, E., Bellows, S., Boesch, S., Bressman, S. B., Duque, K. R., Espay, A. J., ... König, I. R. (2024). Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies. Movement Disorders, 39(11), 2110-2116. https://doi.org/10.1002/mds.29968

@article{c651fdf114534c9b8990e84665ddd37f,

title = "Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies",

abstract = "Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. Conclusions: Moderate single-nucleotide polymorphism–based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis.",

keywords = "GWAS, age at onset, case–control, clinical score, isolated dystonia",

author = "Laabs, {Bj{\"o}rn Hergen} and Katja Lohmann and Vollstedt, {Eva Juliane} and Tobias Reinberger and Nuxoll, {Lisa Marie} and Gamze Kilic-Berkmen and Perlmutter, {Joel S.} and Sebastian Loens and Carlos Cruchaga and Andre Franke and Valerija Dobricic and Frauke Hinrichs and Anne Gr{\"o}zinger and Eckart Altenm{\"u}ller and Steven Bellows and Sylvia Boesch and Bressman, {Susan B.} and Duque, {Kevin R.} and Espay, {Alberto J.} and Andreas Ferbert and Feuerstein, {Jeanne S.} and Samuel Frank and Thomas Gasser and Bernhard Haslinger and Robert Jech and Frank Kaiser and Christoph Kamm and Katja Kollewe and K{\"u}hn, {Andrea A.} and LeDoux, {Mark S.} and Ebba Lohmann and Abhimanyu Mahajan and Alexander M{\"u}nchau and Trisha Multhaupt-Buell and Alexander Pantelyat and {Pirio Richardson}, {Sarah E.} and Deborah Raymond and Reich, {Stephen G.} and {Saunders Pullman}, Rachel and Barbara Schormair and Nutan Sharma and Sichani, {Azadeh Hamzehei} and Kristina Simonyan and Jens Volkmann and {Wagle Shukla}, Aparna and Juliane Winkelmann and Wright, {Laura J.} and Michael Zech and Zeuner, {Kirsten E.} and Simone Zittel and Meike Kasten and Sun, {Yan V.} and Tobias B{\"a}umer and Norbert Br{\"u}ggemann and Ozelius, {Laurie J.} and Jinnah, {Hyder A.} and Christine Klein and K{\"o}nig, {Inke R.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2024",

month = nov,

doi = "10.1002/mds.29968",

language = "English",

volume = "39",

pages = "2110--2116",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley & Sons Inc.",

number = "11",

}

Laabs, BH, Lohmann, K, Vollstedt, EJ, Reinberger, T, Nuxoll, LM, Kilic-Berkmen, G, Perlmutter, JS, Loens, S, Cruchaga, C, Franke, A, Dobricic, V, Hinrichs, F, Grözinger, A, Altenmüller, E, Bellows, S, Boesch, S, Bressman, SB, Duque, KR, Espay, AJ, Ferbert, A, Feuerstein, JS, Frank, S, Gasser, T, Haslinger, B, Jech, R, Kaiser, F, Kamm, C, Kollewe, K, Kühn, AA, LeDoux, MS, Lohmann, E, Mahajan, A, Münchau, A, Multhaupt-Buell, T, Pantelyat, A, Pirio Richardson, SE, Raymond, D, Reich, SG, Saunders Pullman, R, Schormair, B, Sharma, N, Sichani, AH, Simonyan, K, Volkmann, J, Wagle Shukla, A, Winkelmann, J, Wright, LJ, Zech, M, Zeuner, KE, Zittel, S, Kasten, M, Sun, YV, Bäumer, T, Brüggemann, N, Ozelius, LJ, Jinnah, HA, Klein, C & König, IR 2024, 'Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies', Movement Disorders, vol. 39, no. 11, pp. 2110-2116. https://doi.org/10.1002/mds.29968

TY - JOUR

T1 - Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

AU - Laabs, Björn Hergen

AU - Lohmann, Katja

AU - Vollstedt, Eva Juliane

AU - Reinberger, Tobias

AU - Nuxoll, Lisa Marie

AU - Kilic-Berkmen, Gamze

AU - Perlmutter, Joel S.

AU - Loens, Sebastian

AU - Cruchaga, Carlos

AU - Franke, Andre

AU - Dobricic, Valerija

AU - Hinrichs, Frauke

AU - Grözinger, Anne

AU - Altenmüller, Eckart

AU - Bellows, Steven

AU - Boesch, Sylvia

AU - Bressman, Susan B.

AU - Duque, Kevin R.

AU - Espay, Alberto J.

AU - Ferbert, Andreas

AU - Feuerstein, Jeanne S.

AU - Frank, Samuel

AU - Gasser, Thomas

AU - Haslinger, Bernhard

AU - Jech, Robert

AU - Kaiser, Frank

AU - Kamm, Christoph

AU - Kollewe, Katja

AU - Kühn, Andrea A.

AU - LeDoux, Mark S.

AU - Lohmann, Ebba

AU - Mahajan, Abhimanyu

AU - Münchau, Alexander

AU - Multhaupt-Buell, Trisha

AU - Pantelyat, Alexander

AU - Pirio Richardson, Sarah E.

AU - Raymond, Deborah

AU - Reich, Stephen G.

AU - Saunders Pullman, Rachel

AU - Schormair, Barbara

AU - Sharma, Nutan

AU - Sichani, Azadeh Hamzehei

AU - Simonyan, Kristina

AU - Volkmann, Jens

AU - Wagle Shukla, Aparna

AU - Winkelmann, Juliane

AU - Wright, Laura J.

AU - Zech, Michael

AU - Zeuner, Kirsten E.

AU - Zittel, Simone

AU - Kasten, Meike

AU - Sun, Yan V.

AU - Bäumer, Tobias

AU - Brüggemann, Norbert

AU - Ozelius, Laurie J.

AU - Jinnah, Hyder A.

AU - Klein, Christine

AU - König, Inke R.

PY - 2024/11

Y1 - 2024/11

N2 - Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. Conclusions: Moderate single-nucleotide polymorphism–based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis.

AB - Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. Conclusions: Moderate single-nucleotide polymorphism–based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis.

KW - GWAS

KW - age at onset

KW - case–control

KW - clinical score

KW - isolated dystonia

UR - http://www.scopus.com/inward/record.url?scp=85204039570&partnerID=8YFLogxK

U2 - 10.1002/mds.29968

DO - 10.1002/mds.29968

M3 - Article

AN - SCOPUS:85204039570

SN - 0885-3185

VL - 39

SP - 2110

EP - 2116

JO - Movement Disorders

JF - Movement Disorders

IS - 11

ER -

Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

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Keywords

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