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

. Author manuscript; available in PMC: 2025 Nov 1.

Published in final edited form as: Mov Disord. 2024 Sep 17;39(11):2110–2116. doi: 10.1002/mds.29968

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

Björn-Hergen Laabs ¹, Katja Lohmann ², Eva-Juliane Vollstedt ², Tobias Reinberger ³, Lisa-Marie Nuxoll ¹, Gamze Kilic-Berkmen ⁴, Joel S Perlmutter ⁵, Sebastian Loens ⁶, Carlos Cruchaga ⁷, Andre Franke ⁸, Valerija Dobricic ⁹, Frauke Hinrichs ², Anne Grözinger ², Eckart Altenmüller ¹⁰, Steven Bellows ¹¹, Sylvia Boesch ¹², Susan B Bressman ^13,¹⁴, Kevin R Duque ¹⁵, Alberto J Espay ¹⁵, Andreas Ferbert ¹⁶, Jeanne S Feuerstein ¹⁷, Samuel Frank ¹⁸, Thomas Gasser ^19,²⁰, Bernhard Haslinger ²¹, Robert Jech ²², Frank Kaiser ^23,²⁴, Christoph Kamm ²⁵, Katja Kollewe ²⁶, Andrea A Kühn ²⁷, Mark S LeDoux ^28,²⁹, Ebba Lohmann ^19,²⁰, Abhimanyu Mahajan ³⁰, Alexander Münchau ⁶, Trisha Multhaupt-Buell ³¹, Alexander Pantelyat ³², Sarah E Pirio Richardson ³³, Deborah Raymond ¹³, Stephen G Reich ³⁴, Rachel Saunders Pullman ^13,¹⁴, Barbara Schormair ^35,³⁶, Nutan Sharma ³¹, Azadeh Hamzehei Sichani ^14,³⁷, Kristina Simonyan ^14,^30,^31,³⁷, Jens Volkmann ³⁸, Aparna Wagle Shukla ³⁹, Juliane Winkelmann ^35,^36,⁴⁰, Laura J Wright ⁴¹, Michael Zech ^35,³⁶, Kirsten E Zeuner ⁴², Simone Zittel ⁴³, Meike Kasten ^2,⁴⁴, Yan V Sun ⁴⁵, Tobias Bäumer ⁶, Norbert Brüggemann ⁴⁶, Laurie J Ozelius ³¹, Hyder A Jinnah ⁴, Christine Klein ^2,^*, Inke R König ^1,^*

¹Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany

²Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

³Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany

⁴Department of Neurology, Emory University, Atlanta, Georgia, USA

⁵Department of Neurology, Radiology and Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA

⁶Institute of Systems Motor Science, CBBM, University of Lübeck, Lübeck, Germany

⁷Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA

⁸Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany

⁹Lübeck Interdisciplinary Platform for Genome Analysis, University of Lübeck, Lübeck, Germany

¹⁰Institute of Music Physiology and Musician’s Medicine, Hanover University of Music, Drama and Media, Hanover, Germany

¹¹Parkinson’s Disease Center and Movement Disorder Clinic, Baylor College of Medicine, Houston, Texas, USA

¹²Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria

¹³Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York, USA

¹⁴Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

¹⁵James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

¹⁶Department of Neurology, Kassel School of Medicine, Klinikum Kassel, Kassel, Germany

¹⁷Department of Neurology, School of Medicine, University of Colorado, Aurora, Colorado, USA

¹⁸Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

¹⁹Department of Neurology, University of Tübingen, Tübingen, Germany

²⁰Hertie Institute for Clinical Brain Research and DZNE, University of Tübingen, Tübingen, Germany

²¹Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany

²²Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic

²³Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany

²⁴Essener Zentrum für Seltene Erkrankungen, University Hospital Essen, Essen, Germany

²⁵Department of Neurology, University Medical Centre Rostock, Rostock, Germany

²⁶Clinic for Neurology, Hannover Medical School, Hannover, Germany

²⁷Department of Neurology and Experimental Neurology, Charité–University Medicine, Berlin, Germany

²⁸Veracity Neuroscience LLC, Memphis, Tennessee, USA

²⁹Department of Psychology, University of Memphis, Memphis, Tennessee, USA

³⁰Department of Neurological Sciences, RUSH University, Chicago, Illinois, USA

³¹Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

³²Department of Neurology, Johns Hopkins Medicine, Baltimore, Maryland, USA

³³Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA

³⁴University of Maryland School of Medicine, Baltimore, Maryland, USA

³⁵Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany

³⁶Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany

³⁷Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA

³⁸Department of Neurology, University Hospital Würzburg, Würzburg, Germany

³⁹Department of Neurology, University of Florida, Gainesville, Florida, USA

⁴⁰Munich Cluster for Systems Neurology, SyNergy, Munich, Germany

⁴¹Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

⁴²Clinic for Neurology, Christian-Albrechts-University, Kiel, Germany

⁴³Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

⁴⁴Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany

⁴⁵Department of Epidemiology, Emory University Rollins School of Public Health, Emory University, Atlanta, Georgia, USA

⁴⁶Department of Neurology, University of Lübeck, Lübeck, Germany

Correspondence to: Prof. Dr. Christine Klein, Institute of Neurogenetics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. christine.klein@uni-luebeck.deProf Dr. Inke R. König, Institute of Medical Biometry and Statistics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. inke.koenig@uni-luebeck.de

Björn-Hergen Laabs, Katja Lohmann, and Eva-Juliane Vollstedt contributed equally to this work.

Christine Klein and Inke R. König are cosenior authors and contributed equally to this work.

Author Roles

(1) Research project: A. Conception and design, B. Organization, C. Data acquisition and analysis; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Drafting a significant portion of the manuscript and/or figures, B. Review and critique.

B.-H.L.: 1A, 1B, 2A, 2B, 3A

K.L.: 1A, 1B, 1C, 2C, 3A

E.-J.V.: 1A, 1B, 1C, 2C, 3B

T.R.: 1C, 2A, 2C, 3B

L.-M.N.: 1C, 2B, 3A, 3B

G.K.-B.: 1B, 1C, 2C, 3B

S.L.: 1B, 1C, 2C, 3B

C.C.: 1C, 2A, 2C, 3B

A. Franke: 1B, 1C, 2C, 3B

V.D.: 1B, 2C, 3B

F.H.: 1C, 2C, 3B

A.G.: 1C, 2C, 3B

E.A.: 1C, 2C, 3B

S. Bellows: 1C, 2C, 3B

S. Boesch: 1C, 2C, 3B

S.B.B.: 1C, 2C, 3B

K.R.D.: 1C, 2C, 3B

A.J.E.: 1C, 2C, 3B

A. Ferbert: 1C, 2C, 3B

J.S.F.: 1C, 2C, 3B

S.F.: 1C, 2C, 3B

T.G.: 1C, 2C, 3B

B.H.: 1C, 2C, 3B

R.J.: 1C, 2C, 3B

F.K.: 1B, 2C, 3B

C. Kamm: 1C, 2C, 3B

K.K.: 1C, 2C, 3B

A.A.K.: 1C, 2C, 3B

M.S.L.: 1C, 2C, 3B

E.L.: 1C, 2C, 3B

A. Mahajan: 1C, 2C, 3B

A. Münchau: 1C, 2C, 3B

T.M.-B.: 1C, 2C, 3B

A.P.: 1C, 2C, 3B

S.E.P.R.: 1C, 2C, 3B

D.R.: 1C, 2C, 3B

S.R.: 1C, 2C, 3B

R.S.P.: 1C, 2C, 3B

B.S.: 1C, 2C, 3B

N.S.: 1C, 2C, 3B

A.H.S.: 1C, 2C, 3B

K.S.: 1C, 2C, 3B

J.V.: 1C, 2C, 3B

A.W.S.: 1C, 2C, 3B

J.W.: 1C, 2C, 3B

L.J.W.: 1C, 2C, 3B

M.Z.: 1C, 2C, 3B

K.E.Z.: 1C, 2C, 3B

S.Z.: 1C, 2C, 3B

M.K.: 1B, 1C, 2C, 3B

Y.V.S.: 1C, 2A, 2C, 3B

T.B.: 1B, 1C, 2C, 3B

J.S.P.: 1B, 1C, 2C, 3B

N.B.: 1B, 1C, 2C, 3B

L.J.O.: 1B, 1C, 2C, 3B

H.A.J.: 1B, 1C, 2C, 3A

C. Klein: 1A, 1B, 1C, 2C, 3A

I.R.K.: 1A, 1B, 2A, 2C, 3A

PMCID: PMC11975433 NIHMSID: NIHMS2067063 PMID: 39287592

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: isolated dystonia, GWAS, age at onset, clinical score, case–control

Genetic factors contributing to isolated dystonia^1,2 are largely unknown. Notably, 25% of patients with various forms of isolated dystonia also have relatives with dystonia, suggesting a substantial genetic contribution.^3,4 Although several monogenic causes have been the molecular pathogenesis in only a minority of patients, mostly those with early onset and additional clinical features.^6,7 In contrast, genetic risk factors that are thought to contribute to the disease in the remainder of patients are largely unknown. Candidate-based association studies in dystonia were not insightful.⁸ Genome-wide association studies (GWASs) in large patient–control samples are considered effective for the hypothesis-free identification of genetic risk variants. Because dystonia is a relatively rare disorder, only three rather small GWASs have been reported to date, including 158, 212, and 919 patients,^9-11 and focused on either patients with cervical^9,10 or musicians’ dystonia.¹¹ Potential candidates could not be confirmed unequivocally.^10,12,13 Given these overall inconclusive results and limitations, we performed a larger GWAS in different types of isolated dystonia and carried out subgroup analyses.

Participants and Methods

Study Participants

We included 4303 patients with dystonia and 2362 healthy controls. Samples were mainly recruited in the United States and Germany (Supporting Information Tables S1 and S2). All samples were of European ancestry, as confirmed by principal-component analysis against 1000Genomes. All participants gave written informed consent and underwent a standardized neurological examination by a movement disorder specialist. For the replication of potential hits, we used existing genotype data from 736 German dystonia patients (Affymetrix Axiom or Illumina Global Screening Array arrays). Patients with secondary causes of dystonia or monogenic dystonia were excluded. The study was approved by the Ethics Committees of all participating clinical centers.

First, we performed a case–control association study. Next, we carried out subgroup analyses in patients with available information including age at onset (AAO; as a continuous variable) and a newly developed clinical score scaling the degree of presumed genetic burden⁶ with a maximum of 6 points as follows: family history (yes: 2 points; no: 0 points), AAO (<21 years: 2 points; 21–50 years: 1 point; >50 years: 0 points), and distribution of dystonic features (generalized: 2 points; segmental/multifocal: 1 point; focal: 0 points).

Further, we analyzed association with AAO and the clinical score in two patient subgroups based on the site of onset (Table S2), that is, craniocervical onset and onset in the upper extremities. Final sample sizes and demographic information for each analysis are given in Table 1, and a flow chart depicting sample exclusion is provided in Supporting Information Figure S9.

TABLE 1.

Sample sizes and demographic characteristics per analysis after quality control

	Origin
	Germany		USA (with European Ancestry)
	Cases	Controls	Cases	Controls
Case–control status
No. of samples	1424	1345	1113	933
Age (mean, SD), y	42.8 (16.3)	55.5 (14.3)	44.8 (15.4)	66.7 (8.9)
Sex
f	817	707	762	501
m	581	638	351	432
u	26	0	0	0
Age at onset (mean, SD), y	42.8 (16.3)	–	44.8 (15.3)	–
No. of samples	1277	–	1253	–
Sex
f	761	–	848	–
m	515	–	405	–
u	1	–	0	–
Age at craniocervical onset (mean, SD), y	46.3 (15.3)	–	45.2 (14.6)	–
No. of samples	612	–	1006	–
Sex
f	413	–	747	–
m	199	–	259	–
Age at upper extremities onset (mean, SD), y	36.4 (17.4)	–	36.1 (17.7)	–
No. of samples	139	–	187	–
Sex
f	72	–	108	–
m	67	–	79	–
Clinical score (mean, SD)	1.34 (1.13)	–	1.28 (1.10)	–
No. of samples	1313	–	1080	–
Age (mean, SD), y	56.7 (14.6)	–	59.8 (12.9)	–
Sex
f	787	–	737	–
m	525	–	343	–
u	1	–	0	–
Clinical score (craniocervical onset) (mean, SD)	1.37 (1.14)	–	1.27 (1.08)	–
No. of samples	576	–	847	–
Age (mean, SD), y	60.0 (12.6)	–	61.0 (11.5)	–
Sex
f	387	–	637	–
m	189	–	210	–
Clinical score (upper extremities onset) (mean, SD)	1.54 (1.18)	–	1.83 (1.34)	–
No. of samples	142	–	169	–
Age (mean, SD), y	54.1 (15.0)	–	55.3 (14.6)	–
Sex
f	73	–	99	–
m	69	–	70	–

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Abbreviations: SD, standard deviation; f, female; m, male; u, unknown.

Genetic and Statistical Analyses

For the GWAS, blood-derived DNA was analyzed by genome-wide SNP (single-nucleotide polymorphism) genotyping using the Infinium Global Screening Array (Illumina Inc.) for all but the US control subjects, who were genotyped using the Infinium Global Diversity Array (GDA; Illumina Inc.). After quality control and imputation (for details, see Supporting Information Methods in Data S1), we applied SNPTEST v.2.5.1¹⁴ for analysis of each cohort (German, US) separately, using logistic regression models for the overall affected status and linear regression models for the patient-only analyses. Details on the methods and quality control are given in the Supporting Information.

To identify variants with similar effects in the German and US cohorts, we combined both results in respective meta-analyses (META v1.7¹⁴) using an inverse-variance method based on a fixed-effects model.

All variants with P < 5 × 10⁻⁸ were considered genome-wide significant to account for multiple testing based on a Bonferroni correction per GWAS. A potentially meaningful GWAS signal was defined to require at least five SNPs with P < 5 × 10⁻⁵.

In addition, we conducted a power estimation for the case–control, the AAO, and the clinical score GWAS.

Finally, we used GCTA¹⁵ to estimate SNP-based heritability in our datasets. For heritability estimation of case–control status, we assumed a prevalence of idiopathic dystonia of 16.4/100,000.¹⁶ Heritability was estimated in each cohort separately and combined using the inverse variance–weighted method for meta-analyses.

Replication Analyses

We tested single SNPs with genome-wide significance in the case-only analyses from regions with at least five SNPs with P <5 × 10⁻⁵ in the meta-analyses using a previously genotyped European replication sample with 736 dystonia cases. The same models were applied as before, except for the adjustment for principal components.

Results

Genome-Wide Association Analyses

In the Aiation studies, there were no strong genome-wide significantly associated signals (Fig. 1, Supporting Information Figs. S1-S3). All suggestive signals are listed in Table S3. Noteworthy hits, also from a functional point of view, that is, predicted gene function overlapping with pathways known to be altered in dystonia,¹⁷ included rs77507424 (minor allele frequency [MAF] = 0.05; Beta = 4.39 years; P = 2.55 × 10⁻⁷) on chromosome 5 and rs2536490 (MAF = 0.09; Beta = 3.85 years; P = 5.79 × 10⁻⁷) on chromosome 7 for the AAO association study. The former signal harbors PDE6A, encoding a phosphodiesterase. Phosphodiesterases have been shown to regulate striatocortical basal ganglia circuitry and movement control via cyclic adenosine monophosphate (cAMP) signaling,^17,18 and pathogenic variants in PDE10A have been linked to dystonic symptoms. The signal on chromosome 7 is located in PRKAR2B that has also been linked to cAMP signaling.^19,20

In patients with craniocervical onset (n = 1618), one variant (rs3010282) on chromosome 6 (MAF = 0.30; Beta = −4.19 years; P = 2.47 × 10⁻⁹) was genome-wide significantly associated with AAO (Supporting Information Fig. S4) and is located within a long noncoding RNA gene (ENSG00000226571). Two additional SNPs were considered candidates: rs9319387 (MAF = 0.49; Beta = −3.21 years; P = 2.27 × 10⁻⁷) on chromosome 13 and rs3744730 (MAF = 0.02; Beta = −7.86 years; P = 3.06 × 10⁻⁷) on chromosome 17 (Table S3). The nearest genes to the former signal are POLR1D (primarily expressed in skin²¹) and NPM1P4, a pseudogene. The signal on chromosome 17 is located in VPS53, encoding a vacuolar protein sorting protein involved in recycling endocytic vesicles.²²

In patients with onset in the upper extremities (n = 326), we found one variant (rs7907011) on chromosome 10 that showed genome-wide significance (MAF = 0.29; Beta = −13.74 years; P = 3.55 × 10⁻⁸) (Fig. S4) within LOXL4, encoding a lysyl oxidase that is relevant to the extracellular matrix and development.²³

Using the clinical score in cases with craniocervical onset (n = 1423), one genome-wide significant variant (rs3802288) was identified on chromosome 8 (MAF= 0.06; Beta = 0.66; P = 1.19 × 10⁻⁸) in ASPH (a gene primarily expressed in brain and retina²¹).

Finally, one variant (rs77695916; MAF = 0.01; Beta = 1.80; P = 4.48 × 10⁻⁸) on chromosome 5 was genome-wide significantly associated with the clinical score in patients with onset in the upper extremities (n = 311). The signal harbors MFAP3, which is primarily expressed in brain and skin.²¹

Replication Analyses

None of the 14 SNPs in the replication analysis was associated with the respective trait suggested in the initial GWAS phase at a significance level of P < 0.05/14 = 0.0036. Detailed results on replication can be found in Supporting Information Table S3.

Power Estimation

With the case–control meta-analyses, we could have detected common variants (MAF > 20%) with an odds ratio ≥1.5 with a power of >90%. The power was also >90% to detect common variant associations with an effect of 4 years on AAO or 0.4 point on the clinical score, respectively. Detailed results on statistical power are shown in Supporting Information Figure S8.

Heritability Analysis

Overall, we observed moderate heritability of 14% for case–control status, 24% for AAO, and 19% for the clinical score. This means that <25% of the variance in the three different traits can be explained by the genotyped and imputed SNPs.

Discussion

This study aimed to identify genetic risk factors in isolated dystonia. We included a large sample (4108 isolated dystonia patients and 2357 healthy control subjects) and conducted multiple GWASs. Despite being the largest GWAS study to date of isolated dystonia, no robust, replicable associations were found in the overall comparison of cases and control subjects, AAO, or clinical score. Although there was <60% availability of information in the patients to calculate the clinical score (AAO, family history, distribution of dystonia), the study had an overall high power to detect meaningful effects. Notably, associations from previous genome-wide analyses have not been replicated. Furthermore, analyses for AAO and clinical score in subgroups of patients stratified for site at onset yielded several candidate hits. They should be followed up in subsequent studies with larger samples.

Despite the strengths of our study (largest sample size, sufficient power, clinical score, analyses of subgroups), there were several limitations. First, the study included only individuals of European ancestry, limiting the generalizability of the results to other populations. Second, other possible contributing factors such as environmental exposures or epigenetic modifications were not assessed. Third, although 10 genetic principal components were used to decrease population stratification bias, they might have reduced the power to find significantly associated SNPs. Finally, different arrays were used in the US cohort for cases and control subjects, which could have led to batch effects. However, we applied very strict quality criteria to overcome potential biases.

Notably, this study showed two important lessons and helped develop a new hypothesis regarding the impact of genetic variants for isolated dystonia in Europeans. First, there is likely high polygenicity, that is, many risk variants, including rare variants, with relatively small effects contributing to the development of dystonia, as has been demonstrated for other diseases, such as schizophrenia.²⁴ Thus, a much larger sample size would be required to identify the impact of common variants. In addition, sequencing–based GWAS (eg, whole–genome sequencing– based GWAS) might identify risk factors by detecting rarer variants and other variant types such as copy number variants. Along these lines, the heritability estimate indicated that <25% of the variance addressed by our GWAS can be attributed to the analyzed common variants. Second, although we included only participants with isolated dystonia and performed subgroup analyses, the included participants may still be heterogeneous with distinct biological mechanisms underlying their dystonia,²⁵ involving different sets of risk identification. To define molecular–based subgroups, the identification of meaningful biomarkers, which are currently unavailable, would be a prerequisite.

This study, consistent with prior smaller GWASs, did not demonstrate robust genetic risk factors for isolated dystonia, suggesting that the risk factors for dystonia are likely more complex and may involve rare variants. Because it is not feasible to significantly enlarge the sample size, we need alternative approaches to identify further genetic contributions to dystonia, including testing other ethnicities, evaluating low–frequency variants with small effect sizes by genome sequencing, and aiming for a molecularly driven stratification of our patients.

Supplementary Material

NIHMS2067063-supplement-Supplementary_Material.zip^{(1.1MB, zip)}

Acknowledgments:

This study was supported by the Deutsche Forschungsgemeinschaft (FOR 2488 to C.K., N.B., K.L., and I.R.K.). Recruitment of cases through the Dystonia Coalition and preliminary analyses were supported by National Institutes of Health (NIH) Grants NS095445, NS116025, and NS065701 from the National Institutes of Neurological Disorders and Stroke and Grant TR001456 from the National Center for Advancing Translational Sciences. The DysTract consortium received funding from the Federal Ministry of Education and Research in Germany (BMBF; Grant 01GM1514A). This study was also supported by the NIH (Grant P01NS087997 to L.J.O. and N.S.; Grants R01DC011805, R01DC012545, and R01NS088160 to K.S.; and Grant R01NS026656 to S.B.B.). Genotyping of samples in this study received infrastructure support through the DFG Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (Grant EXC2167 to A.F.). R.J. was supported by the National Institute for Neurological Research, Czech Republic, Programme EXCELES, ID Project LX22NPO5107, funded by the European Union–Next Generation EU and also by Charles University: Cooperation Program in Neuroscience. M.Z. acknowledges grant support by the European Joint Programme on Rare Diseases (EJP RD Joint Transnational Call 2022) and the BMBF (Bonn, Germany), awarded to the project PreDYT (PREdictive biomarkers in DYsTonia, 01GM2302), by the BMBF and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder, as well as by the Technical University of Munich–Institute for Advanced Study. The Dystonia Coalition is part of the NIH Rare Diseases Clinical Research Network. Funding and/or programmatic support for this project has been provided by NS065701, TR001456, and NS116025 from the NIH Office of Rare Diseases Research in the National Center for Advancing Translational Sciences and the National Institute of Neurological Disorders and Stroke. We acknowledge the contribution of Jeanette Erdmann to the work presented in this article. She substantially contributed to the conception of the project and acquisition of the data. However, she sadly passed away while data interpretation and manuscript drafting were ongoing; she therefore was no longer able to critically revise and give approval to the final version of the manuscript, nor can she be held accountable for the work. Following the suggestions of the literature (https://jme.bmj.com/content/45/5/331.long) and because the authors view it as an open question whether she would have approved the final version of the manuscript in its present form, she is not included as an author.

Financial Disclosures

Carlos Cruchaga has received research support from GSK, EISAI, Danaher, Biogen, Alector; and Centene; receives research support from the National Institutes of Health (NIH; R01AG044546, P01AG003991, RF1AG053303, RF1AG058501, and U01AG058922), Chan Zuckerberg Initiative, The Michael J. Fox Foundation (LI, CC), Cure Alzheimer’s Fund, Alzheimer’s Association Zenith Fellows Award (ZEN-22-848,604), and an anonymous foundation; is a member of the advisory board of GSK, AbbVie, Circular Genomics, and ADMit; and owns Circular Genomics stock. Kevin R. Duque has received honoraria from the Parkinson’s Foundation for translation support. Alberto J. Espay has received grant support from the NIH and The Michael J. Fox Foundation; has received personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Supernus (formerly, USWorldMeds), NeuroDiagnostics, Inc. (SYNAPS Dx), and Herantis Pharma; and has received publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; cofounded REGAIN Therapeutics; and is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” Christoph Kamm has received honoraria as a consultant for Ipsen, Roche, and Biogen, outside of the submitted work. Mark S. LeDoux has been a consultant for Supernus and Solstice; speaker for Teva Pharmaceutical Industries, Neurocrine, Amneal, USWorldMeds, Supernus, Kyowa Kirin, Otsuka America Pharmaceutical, and Lundbeck; receives publishing royalties from Elsevier (Animal Models of Movement Disorders and Movement Disorders: Genetics and Models) and TheBookPatch (Parkinson’s Disease Poetry); and has been funded by the NIH, Axovant Sciences, Wave Life Sciences, Teva Pharmaceutical Industries, Pharma Two B, Revance, Cerevel, Annovis, Aeon, NeuroDerm, Sage Therapeutics, Inhibikinase Therapeutics, UCB Pharma, Intra-Cellular Therapies, Dystonia Medical Research Foundation, and Benign Essential Tremor Research Foundation. Abhimanyu Mahajan’s research has been funded by the Dystonia Medical Research Foundation, Sunflower Parkinson’s Disease Foundation, and the Parkinson’s Foundation, outside of the submitted work. Alexander Pantelyat reports grant support from NIH Grants K23 AG059891, U01 NS102035 and R44 AG080861 as principal investigator (PI)/co-PI; serves on the Scientific Advisory Board of Medrhythms, Inc.; is on the board of CurePSP; and has received royalties from Springer. Stephen G. Reich has received speakers’ honoraria from the International Parkinson’s Disease and Movement Disorders Society and the Americal Academy of Neurology; book royalties from Oxford, Springer, and Informa; and consulting fees from Best Doctors and UpToDate. Sarah E. Pirio Richardson has received honoraria for lectures from the International Parkinson’s Disease and Movement Disorders Society and the American Academy of Neurology; serves on the Scientific Advisory Boards for private foundations including the Benign Essential Blepharospasm Research Foundation and the Dystonia Medical Research Foundation; and has received royalties from Springer. Kristina Simonyan receives funding from the NIH (Grants R01NS088160, R01NS124228, R01DC011805, R01DC012545, R01DC019353, P50DC01990, and R01DE030464) and the Department of Defense; serves on the Scientific Advisory Board of the Tourette Association of America and the Voice Foundation; and has received consulting fees from Jazz Pharmaceuticals Inc. and AbbVie Inc. Aparna Wagle Shukla reports grant support from the NIH (R01 NS122943 as PI and R01 NS121120-01 as a co-investigator); reports past funding from Benign Essential Blepharospasm Research foundation, Dystonia Coalition, Dystonia Medical Research foundation, and National Organization for Rare Disorders; has received consultant fees from Merz, Jazz, and Acadia; and is the current Vice President for the Tremor Research Group and recent advisor for Supernus and Biogen-Sage. Norbert Brüggemann received honoraria and support for participation in advisory boards from Abbott, AbbVie, Biogen, Biomarin, Bridgebio, Centogene, Esteve, Ipsen, Merz, and Zambon. H.A. Jinnah has active or recent grant support (recent, active, or pending) from the US government (NIH), private philanthropic organizations (Cure Dystonia Now, Lesch–Nyhan Syndrome Children’s Research Foundation), and industry (AbbVie, Addex, Aeon, Sage, Jazz); has served on advisory boards or as a consultant for AbbVie, Addex, Allergan, Ipsen, Merz, and Revance; has received stipends for administrative work from the International Parkinson’s Disease and Movement Disorders Society; has also served on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, the Dystonia Medical Research Foundation, and the Tourette Association of America; is PI for the Dystonia Coalition, which has received the majority of its support through the NIH (Grants NS116025 and NS065701 from the National Institutes of Neurological Disorders and Stroke; Grant TR001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). Christine Klein serves as a medical advisor to Centogene and Retromer Therapeutics and received speakers’ honoraria from Bial and Desitin.

Footnotes

Relevant conflicts of interest/financial disclosures: C.C. has received research support from GSK, EISAI, Danaher, Biogen, Alector, and Centene; receives research support from the National Institutes of Health (NIH), Chan Zuckerberg Initiative, The Michael J. Fox Foundation, Cure Alzheimer’s Fund, Alzheimer’s Association Zenith Fellows Award, and an anonymous foundation; is a member of the advisory board of GSK, AbbVie, Circular Genomics, and ADMit; and owns Circular Genomics stock. K.R.D. has received honoraria from the Parkinson’s Foundation for translation support. A.J.E. has received grant support from the NIH and The Michael J. Fox Foundation; has received personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Supernus (formerly USWorldMeds), NeuroDiagnostics, Inc. (SYNAPS Dx), and Herantis Pharma; has received publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; cofounded REGAIN Therapeutics; and is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” C. Kamm has received honoraria as a consultant for Ipsen, Roche, and Biogen, outside of the submitted work. M.S.L. has been a consultant for Supernus and Solstice; has been a speaker for Teva Pharmaceutical Industries, Neurocrine, Amneal, USWorldMeds, Supernus, Kyowa Kirin, Otsuka America Pharmaceutical, and Lundbeck; receives publishing royalties from Elsevier (Animal Models of Movement Disorders, and Movement Disorders: Genetics and Models) and TheBookPatch (Parkinson’s Disease Poetry); and his research has been funded by the NIH, Axovant Sciences, Wave Life Sciences, Teva Pharmaceutical Industries, Pharma Two B, Revance, Cerevel, Annovis, Aeon, NeuroDerm, Sage Therapeutics, Inhibikinase Therapeutics, UCB Pharma, Intra-Cellular Therapies, Dystonia Medical Research Foundation, and Benign Essential Tremor Research Foundation. A. Mahajan has been funded by the Dystonia Medical Research Foundation, Sunflower Parkinson’s Disease Foundation, and the Parkinson’s Foundation, outside of the submitted work. A.P. reports grant support from the NIH as principal investigator (PI)/co-PI; serves on the Scientific Advisory Board of Medrhythms, Inc.; is on the board of CurePSP; and has received royalties from Springer. S.G.R. has received speakers’ honoraria from the International Parkinson’s Disease and Movement Disorders Society and the American Academy of Neurology; book royalties from Oxford, Springer, and Informa; and consulting fees from Best Doctors and UpToDate. S.E.P.R. has received honoraria for lectures from the International Parkinson’s Disease and Movement Disorders Society and the American Academy of Neurology; serves on the Scientific Advisory Boards for private foundations including the Benign Essential Blepharospasm Research Foundation and the Dystonia Medical Research Foundation; and has received royalties from Springer. K.S. receives funding from the NIH and the Department of Defense; serves on the Scientific Advisory Board of the Tourette Association of America and the Voice Foundation; and received consulting fees from Jazz Pharmaceuticals Inc. and AbbVie Inc. A.W.S. reports grant support from the NIH; has received funding from Benign Essential Blepharospasm Research foundation, Dystonia Coalition, Dystonia Medical Research foundation, and National Organization for Rare Disorders; has received consultant fees from Merz, Jazz, and Acadia; and is the current Vice President for the Tremor Research Group and recent advisor for Supernus and Biogen-Sage. N.B. has received honoraria and support for participation in advisory boards from Abbott, AbbVie, Biogen, Biomarin, Bridgebio, Centogene, Esteve, Ipsen, Merz, and Zambon. H.A.J. has active or recent grant support (recent, active, or pending) from the US government (NIH), private philanthropic organizations (Cure Dystonia Now, Lesch–Nyhan Syndrome Children’s Research Foundation), and industry (AbbVie, Addex, Aeon, Sage, Jazz); has served on advisory boards or as a consultant for AbbVie, Addex, Allergan, Ipsen, Merz, and Revance; has received stipends for administrative work from the International Parkinson’s Disease and Movement Disorders Society; has served on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, the Dystonia Medical Research Foundation, and the Tourette Association of America; and is PI for the Dystonia Coalition, which has received the majority of its support through the NIH. C. Klein serves as a medical advisor to Centogene and Retromer Therapeutics and received speakers’ honoraria from Bial and Desitin. The remaining authors declare no conflicts of interest.

Supporting Data

Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.

Data Availability Statement

The data that support the findings of this study are openly available in GWAS Catalog at https://www.ebi.ac.uk/gwas/home, reference number GCP000887.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material

NIHMS2067063-supplement-Supplementary_Material.zip^{(1.1MB, zip)}

Data Availability Statement

The data that support the findings of this study are openly available in GWAS Catalog at https://www.ebi.ac.uk/gwas/home, reference number GCP000887.

[R1] 1.Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863–873. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Grütz K, Klein C. Dystonia updates: definition, nomenclature, clinical classification, and etiology. J Neural Transm (Vienna) 2021;128:395–404. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Waddy HM, Fletcher NA, Harding AE, Marsden CD. A genetic study of idiopathic focal dystonias. Ann Neurol 1991;29:320–324. [DOI] [PubMed] [Google Scholar]

[R4] 4.Schmidt A, Jabusch H-C, Altenmüller E, et al. Etiology of musician’s dystonia: familial or environmental? Neurology 2009;72:1248–1254. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Lange LM, Gonzalez-Latapi P, Rajalingam R, et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society task force - an update. Mov Disord 2022;37:905–935. [DOI] [PubMed] [Google Scholar]

[R6] 6.Zech M, Jech R, Boesch S, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 2020;19:908–918. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7.Lange LM, Junker J, Loens S, et al. Genotype-phenotype relations for isolated dystonia genes: MDSGene systematic review. Mov Disord 2021;36:1086–1103. [DOI] [PubMed] [Google Scholar]

[R8] 8.Ohlei O, Dobricic V, Lohmann K, et al. Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia. Parkinsonism Relat Disord 2018;57:50–57. [DOI] [PubMed] [Google Scholar]

[R9] 9.Mok KY, Schneider SA, Trabzuni D, et al. Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel. Mov Disord 2014;29:245–251. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] 10.Sun YV, Li C, Hui Q, et al. A multi-center genome-wide association study of cervical dystonia. Mov Disord 2021;36:2795–2801. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R11] 11.Lohmann K, Schmidt A, Schillert A, et al. Genome-wide association study in musician’s dystonia: a risk variant at the arylsulfatase G locus? Mov Disord 2014;29:921–927. [DOI] [PubMed] [Google Scholar]

[R12] 12.Nibbeling E, Schaake S, Tijssen MA, et al. Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia. J Neurol 2015;262:1340–1343. [DOI] [PubMed] [Google Scholar]

[R13] 13.Gômez-Garre P, Huertas-Fernândez I, Câceres-Redondo MT, et al. Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study. Mov Disord 2014;29:1825–1828. [DOI] [PubMed] [Google Scholar]

[R14] 14.Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet 2010;11:499–511. [DOI] [PubMed] [Google Scholar]

[R15] 15.Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 2011;88: 76–82. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] 16.Steeves TD, Day L, Dykeman J, Jette N, Pringsheim T. The prevalence of primary dystonia: a systematic review and meta-analysis. Mov Disord 2012;27:1789–1796. [DOI] [PubMed] [Google Scholar]

[R17] 17.Thomsen M, Lange LM, Zech M, Lohmann K. Genetics and pathogenesis of dystonia. Annu Rev Pathol 2024;19:99–131. [DOI] [PubMed] [Google Scholar]

[R18] 18.Diggle CP, Sukoff Rizzo SJ, Popiolek M, et al. Biallelic mutations in PDE10A Lead to loss of striatal PDE10A and a hyperkinetic movement disorder with onset in infancy. Am J Hum Genet 2016;98: 735–743. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19.Mencacci NE, Kamsteeg E-J, Nakashima K, et al. De novo mutations in PDE10A cause childhood-onset chorea with bilateral striatal lesions. Am J Hum Genet 2016;98:763–771. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20.Rinaldi L, Donne RD, Catalanotti B, et al. Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system. Nat Commun 2019;10:2572. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R21] 21.Porpora M, Sauchella S, Rinaldi L, et al. Counterregulation of cAMP-directed kinase activities controls ciliogenesis. Nat Commun 2018;9:1224. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] 22.Velculescu VE, Zhang L, Vogelstein B, Kinzler KW. Serial analysis of gene expression. Science 1995;270:484–487. [DOI] [PubMed] [Google Scholar]

[R23] 23.Schindler C, Chen Y, Pu J, Guo X, Bonifacino JS. EARP is a multisubunit tethering complex involved in endocytic recycling. Nat Cell Biol 2015;17:639–650. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R24] 24.Asuncion L, Fogelgren B, Fong KS, et al. A novel human lysyl oxidase-like gene (LOXL4) on chromosome 10q24 has an altered scavenger receptor cysteine rich domain. Matrix Biol 2001;20: 487–491. [DOI] [PubMed] [Google Scholar]

[R25] 25.Als TD, Kurki MI, Grove J, et al. Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses. Nat Med 2023;29:1832–1844. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

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

Björn-Hergen Laabs, PhD

Katja Lohmann, PhD

Eva-Juliane Vollstedt, MD

Tobias Reinberger, PhD

Lisa-Marie Nuxoll, MSc

Gamze Kilic-Berkmen, PhD

Joel S Perlmutter, MD

Sebastian Loens, MD

Carlos Cruchaga, PhD

Andre Franke, PhD

Valerija Dobricic, PhD

Frauke Hinrichs

Anne Grözinger, BSc

Eckart Altenmüller, MD

Steven Bellows, MD

Sylvia Boesch, MD, MSc

Susan B Bressman, MD

Kevin R Duque, MD

Alberto J Espay, MD

Andreas Ferbert, MD

Jeanne S Feuerstein, MD

Samuel Frank, MD

Thomas Gasser, MD

Bernhard Haslinger, MD

Robert Jech, MD, PhD

Frank Kaiser, PhD

Christoph Kamm, MD

Katja Kollewe, MD

Andrea A Kühn, MD

Mark S LeDoux, MD, PhD

Ebba Lohmann, MD

Abhimanyu Mahajan, MD, MHS

Alexander Münchau, MD

Trisha Multhaupt-Buell, MS, CGC

Alexander Pantelyat, MD

Sarah E Pirio Richardson, MD

Deborah Raymond, MS, CGC

Stephen G Reich, MD

Rachel Saunders Pullman, MD, MPH, MSc

Barbara Schormair, PhD

Nutan Sharma, MD, PhD

Azadeh Hamzehei Sichani, MA

Kristina Simonyan, MD, PhD, DrMed

Jens Volkmann, MD

Aparna Wagle Shukla, MD

Juliane Winkelmann, MD

Laura J Wright, MA

Michael Zech, MD

Kirsten E Zeuner, MD

Simone Zittel, MD

Meike Kasten, MD

Yan V Sun, PhD

Tobias Bäumer, MD

Norbert Brüggemann, MD

Laurie J Ozelius, PhD

Hyder A Jinnah, MD, PhD

Christine Klein, MD

Inke R König, PhD

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Participants and Methods

Study Participants

TABLE 1.

Genetic and Statistical Analyses

Replication Analyses

Results

Genome-Wide Association Analyses

FIG. 1.

Replication Analyses

Power Estimation

Heritability Analysis

Discussion

Supplementary Material

Acknowledgments: