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Risk Factor Genes in Patients with Dystonia: A Comprehensive Review


Vasileios Siokas,

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, GR
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Athina-Maria Aloizou,

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, GR
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Zisis Tsouris,

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, GR
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Amalia Michalopoulou,

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, GR
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Alexios-Fotios A. Mentis,

Department of Microbiology, University of Thessaly, University Hospital of Larissa, Larissa; Public Health Laboratories, Hellenic Pasteur Institute, Athens, GR
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Efthimios Dardiotis

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, GR
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Background: Dystonia is a movement disorder with high heterogeneity regarding phenotypic appearance and etiology that occurs in both sporadic and familial forms. The etiology of the disease remains unknown. However, there is increasing evidence suggesting that a small number of gene alterations may lead to dystonia. Although pathogenic variants to the familial type of dystonia have been extensively reviewed and discussed, relatively little is known about the contribution of singlenucleotide polymorphisms (SNPs) to dystonia. This review focuses on the potential role of SNPs and other variants in dystonia susceptibility.

Methods: We searched the PubMed database for peer-reviewed articles published in English, from its inception through January 2018, that concerned human studies of dystonia and genetic variants. The following search terms were included: ‘‘dystonia’’ in combination with the following terms: 1) ‘‘polymorphisms’’ and 2) ‘‘SNPs’’ as free words.

Results: A total of 43 published studies regarding TOR1A, BDNF, DRD5, APOE, ARSG, NALC, OR4X2, COL4A1, TH, DDC, DBH, MAO, COMT, DAT, GCH1, PRKRA, MR-1, SGCE, ATP1A3, TAF1, THAP1, GNAL, DRD2, HLA-DRB, CBS, MTHFR, and MS genes, were included in the current review.

Discussion: To date, a few variants, which are possibly involved in several molecular pathways, have been related to dystonia. Large cohort studies are needed to determine robust associations between variants and dystonia with adjustment for other potential cofounders, in order to elucidate the pathogenic mechanisms of dystonia and the net effect of the genes.

How to Cite: Siokas V, Aloizou A-M, Tsouris Z, Michalopoulou A, Mentis A-FA, Dardiotis E. Risk Factor Genes in Patients with Dystonia: A Comprehensive Review. Tremor and Other Hyperkinetic Movements. 2019;8:559. DOI:
  Published on 09 Jan 2019
 Accepted on 20 Nov 2018            Submitted on 12 Mar 2018


Dystonia is a movement disorder with high heterogeneity regarding phenotypic appearance and etiology.1 The prevalence of dystonia is estimated to be 16:100,000.2,3 In 2013, a new general definition and classification of dystonia were introduced by an international panel of dystonia experts.4 The two main axes of this classification are considered to be the etiology and the clinical features.4 However, the pathophysiology and cause of most dystonia cases remain largely unknown.5

A polymorphism is a variation in the DNA sequence that occurs in a population with a frequency of 1 % or higher.6,7 When a variation occurs in a single nucleotide, at a specific position in the genome, it is called an SNP (single-nucleotide polymorphism).8,9 SNPs can occur within coding sequences of genes, non-coding sequences, introns, or the regions between genes (also known as intergenic regions).10,11 An SNP across a coding sequence of a gene can be characterized as synonymous (when the protein sequence is not affected) and non-synonymous (when the amino acid sequence of the protein is altered).10,12 The non-synonymous SNPs are divided into missense (when they result in a different amino acid) and nonsense (when they result in a premature stop codon).10,12 Recently, it has been recommended that both terms, “mutation” and “polymorphism”, be replaced by the term “variant”.13,14 An additional modifier (e.g. pathogenic, benign) to the term “variant” should be used, in order for its pathogenic or benign effect to be declared.13,14

The importance of genetic factors was unambiguously demonstrated with the identification of causative pathogenic variants in monogenic cases of familial dystonia under the autosomal dominant, autosomal recessive, or X-linked mode of inheritance.3 Furthermore, a few candidate gene association studies (CGASs) have suggested that the presence of specific genetic loci may confer susceptibility to dystonia.15 Genetic variations may affect dystonia’s phenotypic appearance, age at onset, and spread to adjacent body regions, and may also affect the penetrance of other pathogenic variants suspected for dystonia.15

Previous reviews have mainly discussed the genetics of dystonia in general its monogenic forms and its phenotypic divergence.3,1625 However, genetics of sporadic forms of dystonia with no clearly discernible family history, and results from case–control studies are relatively rarely discussed.15,18,25 Therefore, in the present review article, we discuss the current state of knowledge regarding genetics of dystonia, by emphasizing the CGASs that have linked single nucleotide polymorphisms and variants across genes that predispose to dystonia. Owing to the lack of a widely accepted nomenclature gene classification system for dystonia, we have used gene names for loci identification.26 The main aim of the current comprehensive review is to shed some light on which polymorphisms predispose for dystonia, and to what extent.

Methods: study identification and selection

In order for any potentially relevant study to be identified, we searched through the Pubmed database ( for peer-reviewed articles published in English, from its inception to January 2018, that concerned human studies of dystonia and genetic polymorphisms. The following search terms were included: “dystonia” in combination with 1) “polymorphisms” and 2) “SNPs” as free words. The complete search algorithm is available in the S1 Appendix. The last literature search was performed on February 20, 2018. Additionally, reference lists of retrieved articles were examined in order to identify missing from the initial database search results. The flowchart presenting the selection procedure of the studies is presented in Figure 1. Published studies between 1996 and 2017 were included.

Figure 1 

Flow chart presenting the selection of the studies included in the current review.

The following data were extracted from each study, when possible: author, year of publication, ethnicity of the studied population, numbers of cases and controls, age at disease onset, mean age and gender distribution, tested variants, family history of the participants, screening or not for the TOR1A ∆GAG pathogenic variant, correction for multiple comparisons, assessment of Hardy–Weinberg equilibrium, and the tested dystonia phenotypes.

Results and discussion

Published studies between August 2001 and September 2017 were included. Baseline characteristics from studies regarding TOR1A, BDNF, DRD5, APOE, ARSG, NALC, OR4X2, COL4A1, TH, DDC, DBH, MAO, COMT, DAT, GCH1, PRKRA, MR-1, SGCE, ATP1A3, TAF1, THAP1, GNAL, DRD2, HLA-DRB, CBS, MTHFR, and MS are presented in Supplementary Tables 1–5. GnomAD frequencies ( and the type of individual variants are available at the S2 Appendix.


The TOR1A gene is a five-exon gene that covers an 11-kb region in chromosome 9. The TOR1A protein, called TorsinA, belongs to the family of the AAA+ ATPases. It can be found in the endoplasmic reticulum and the nuclear envelope of most cells,8 including those of the central nervous system.18 The function of TorsinA and how TOR1A gene pathogenic variants lead to dystonia remains largely unknown.27 TorsinA acts mainly as a molecular chaperone.28 The molecular and cellular processes in which TorsinA is involved include the interactions between cytoskeleton and membrane, important functions of the endoplasmic reticulum and the nuclear envelope, and the regulation of cellular lipid metabolism.18,2931 It is known that TorsinA needs to bind to TOR1AIP2 (Torsin 1A Interacting Protein 2) or to Heat Shock Protein Family A (Hsp70) Member 8 (HSPA8) in order to be activated,32 a procedure that is impaired by the GAG deletion, as has been confirmed by crystallography.33,34

TOR1A remains the most extensively studied gene in both monogenic and sporadic forms of dystonia.15 However, results from case–control studies yielded conflicting results, with the association being affected by body distribution, ethnicity, and other phenotypic manifestations. A number of case–control studies have been conducted so far3552 and quite a few TOR1A variants have also been investigated (rs1801968, rs2296793, rs1182, rs3842225, rs13283584, rs11787741, rs13297609, rs2287367, rs1043186, and rs35153737). Apart from case–control studies, a number of variants have been identified through mutational screening (rs766483672, rs80358233, rs75881350, rs1183, rs563498119, rs573629050, rs1045441, rs144572721).53 Additionally, three meta-analyses have been conducted so far examining the effects of TOR1A gene variants on dystonia.15,39,40 The most recent evidence stemming from a meta-analysis, reveals a significant association of the rs1182 (allele frequency [AF] = 0.1666) and the rs1801968 (AF = 0.1236 for the G allele and AF = 4.061e-6 for the C allele) TOR1A variants with the development of focal dystonia (FD) and writer’s cramp (WC) respectively.15 Moreover, variants within 3′-UTR (untranslated region) encoded by exon 5 represent an additional functional genetic locus of TOR1A, though it may be under synergistic action with other TOR1A genetic variants.15 This comes in accordance with a recent case–control study, suggesting an association of the rs35153737 in the 3′-UTR of TOR1A with dystonia; a result, though, that has been attributed to functional variants that are in high linkage disequilibrium (LD).52

From a functional aspect, loci containing the aforementioned variants appear to have consequences; variants across exon 4 and 3′-UTR encoded by exon 5, in particular, appear to overall influence the function of the TOR1A gene.15 More specifically, rs1801968 was confirmed to be associated with reduced penetrance of the ∆GAG pathogenic variant in humans.54,55 Regarding the 3′-UTR of exon 5, there is only some indication that specific variants across this region may have some functional consequences under synergistic action.15,52 Interestingly, based on the results regarding frequencies, computational analyses and function experiments, rs563498119 in the 3′-UTR of TOR1A was reported to change the expression of the TOR1A gene.53 The regulation of TOR1A expression, by mutating the conserved region of the binding site of the human microRNA (hsa-miR-494), where rs563498119 is located, hints towards hsa-miR-494 being a possible therapeutic target.53


Among the major mechanisms in dystonia, the reduced inhibition of the motor system and the increased plasticity are included.56 In greater detail, increased plasticity in the hand representation area of the motor cortex has been observed in focal hand dystonia, blepharospasm (BSP), and cervical dystonia (CD) using high-resolution transcranial stimulation.57 Consequently, abnormal plasticity within certain motor cortical circuits may represent a lineament of adult-onset dystonia forms.57,58

Synaptic plasticity is influenced by the brain-derived neurotrophic factor (BDNF). A common SNP across the BDNF gene within the prodomain region is the rs6265 (G/A) (AF = 0.1896) and it results in the substitution of Val in amino acid position 66 with Met (Val→Met), which may influence synaptic plasticity5961 and is possibly involved in dystonia development. Healthy carriers of the val66met appear to have differences in brain structure and abnormal motor cortex plasticity as well.62,63 Rs6265 has been found to be associated with quite a few diseases such as Parkinson’s disease, Alzheimer disease (AD), schizophrenia, bipolar disease, depressive disorder, and panic disorders, although strong evidence has yet to be presented.6469

The studies that have been conducted so far regarding the role of the rs6265 on dystonia have yielded conflicting results. More precisely, rs6265 has been reported to be associated with CD and BSP in multiethnic and Chinese cohorts respectively.70,71 Additionally, higher frequency of bilateral postural arm tremor in CD patients with the BDNF Met66Met variant than inVal66Met and Val66Val carriers has also been observed.72 However, these results have not been replicated in Serbian, Chinese, Italian, or Caucasian dystonia cohorts.58,7375 To date, two meta-analyses have evaluated the effects of rs6265 variant on dystonia.75,76 The most recent reports a statistically significant overall effect of the AA genotype on the development of idiopathic dystonia.76 However, the lack of reproducibility of the positive results could be attributed, among others, to the culture of null hypothesis significance testing,77 the possible influence of epigenetic mechanisms in the gene function (such as DNA methylation),78 and to the fact that additional variants across the BDNF may regulate the level of serum BDNF and its function.79 BDNF could be considered a potential therapeutic target in dystonia, as in neurological and psychiatric disorders.8082

Apolipoprotein E is the product of the APOE gene, which connects to lipids in order to form lipoproteins. There are at least three alleles (e2, e3, and e4) of the APOE gene, with the commonest one being the e3. The main function of lipoproteins is to package cholesterol and other fats, and transport them throughout tissues including the central nervous system.83 The e4 allele is associated with an increased risk of AD compared with the e3 allele, whereas the e2 allele is associated with decreased risk.84 Like BDNF, APOE may also influence neural plasticity and remodeling.71,85 In a Japanese cohort, E4 carriers were shown to develop dystonia on average approximately 10 years earlier than e4 non-carriers.58 TorsinA is also involved in cellular lipid metabolism.29 Therefore, variants that influence lipid biology may contribute to dystonia. Matsumoto et al.85 suggested that the e4 allele may severely affect neuronal reorganization and this impairment of neuronal repair may contribute to an earlier age of dystonia onset. Consequently, it is possible that variants within TOR1A, BDNF, APOE or even other genes under synergistic action, influence the phenotypic manifestation of dystonia.


Around a hundred missense, nonsense, and frameshift pathogenic variants, throughout most part of the coding region of the “thanatos associated protein domain containing, apoptosis associated protein 1” (THAP1) gene, have been associated with dystonia3,86,87 in a genetically diverse population.18 The THAP1 gene encodes the transcription factor THAP1, a zinc finger protein with an amino-terminal THAP domain, a proline-rich region, and a carboxy-terminal nuclear domain as well.88 THAP1 is thought to regulate the transcription of several key genes, TOR1A included.18,89

Case–control studies regarding THAP1 variants are limited35,40 because of the variety and the rarity of THAP1 variants. Therefore, most findings derive from mutational screening and the comparison between dystonia cases and healthy individuals.86,87,9096 However, there is an indication that the frequency of the C allele of the c.71+126T>C pathogenic variant was elevated in British dystonia patients.90 -237_236GA>TT was also over-represented in dystonia when compared with controls in a European cohort94 but these results could not be replicated.90,91,97 Furthermore, the IVS2-87 A>G (rs11989331, AF = 0.003428) was over-represented in dystonia in an Indian study.95 The MAF of rs200209986 was also found to be significantly higher in dystonic patients (MAF = 0.359%) than in the controls (MAF = 0.0318%, p<0.05) in the Vemula et al.96 study and the 1000 Genomes project (MAF = 0.0916%, p<0.05), but not when compared with the EVS database (MAF = 0.199%, p = 0.13).

The large amount of THAP1 pathogenic variants linked to dystonia may suggest an interplay between environmental and genetic factors.98 Further, the type of work or the exposure to environmental factors, such as pesticides, may possibly predispose to dystonia development in pathogenic variant carriers.21,86,87


GNAL (guanine nucleotide-binding protein subunit alpha L) has been identified as responsible for adult-onset dystonia, which is primarily cervical or cranial.99 A few GNAL variants (rs9303742, rs9675415, rs1895689, rs8095592, rs72865259, rs1647556, rs200508915, rs138151459, rs2071140, rs2071141, rs199571902) have been examined for association with generalized, multifocal, segmental, and focal dystonia.100 Despite the fact that no strong evidence for association with dystonia was found, novel variants are constantly reported in single dystonia patients with various phenotypes,100 leading to approximately 30 different GNAL variants in dystonia patients.3GNAL encodes guanine nucleotide-binding protein G subunit alpha [Gα(olf)]. Gα(olf)is involved in both the direct and indirect pathway to the activation of adenylate cyclase, by coupling dopamine type 1 receptors and the adenosine A2A receptors in medium spiny neurons, respectively.99 In fact, the involvement in the indirect pathway of the activation leads to the activation of adenylyl cyclase type 5 (AC5). AC5 is encoded by the adenylyl cyclase 5 (ADCY5) gene, which was recently reported to be a co-founder of dystonia.101 It is possible that epistasis phenomenon with ADCY5 influences the causative effect of GNAL variants.

Newman at al.40 in 2012, apart from TOR1A and THAP1, which are described in the above sections, genotyped several variants of other genes as well (TAF1, GCH1, MR-1 (PNKD), SGCE, ATP1A3, and PRKRA).40 The results were negative regarding quite a few variants across TAF1, MR-1 (PNKD), SGCE, ATP1A3, and PRKRA, yet weak associations were observed for the rs12147422 (AF = 0.217), rs3759664 (AF = 0.2353), and rs10483639 (AF = 0.2539) of GCH1 (GTP cyclohydrolase 1) variants when the entire, non-homogeneous phenotypic, dystonia group was compared with controls. The lack of reproducibility of these associations could be explained by the low prevalence of dystonia, suggesting the need of collaborative studies.102 Nevertheless, GCH1 belongs to the confirmed causative genes of dopa-responsive dystonia. Additionally, the penetrance of GCH1 pathogenic variants appears to be considerably higher in females than in males.103 The GCH1 gene encodes the rate-limiting enzyme in the biosynthesis of dopamine via the biopterin pathway. GTP cyclohydrolase1 is involved in tetrahydrobiopterin neo-synthesis from GTP, as it catalyzes the first step of this reaction.18 Variants of GHC1 influence enzyme activity, leading to a deficiency in dopamine and serotonin.104 Therefore, a possible role of GCH1 in non-monogenic forms of dystonia should not be dismissed, as scientific reasoning could not be substituted by statistical analysis.105

Finally there is no strong evidence for the association between HLA-DRB variants or variants in the homocysteine pathway (cystathionine β-synthase [CBS], methionine tetrahydrofolate reductase [MTHFR], methionine synthase [MS] genes) with dystonia.50

Dopamine pathway genes (DAT1, DRD1, DRD2, DRD3, DRD4, DRD5, COMT, DAT, TH, MAO-A and -B, DDC, and DBH)

Dystonic movements are considered the result of impaired function and abnormalities of dopaminergic neurotransmission and signaling in the basal ganglia.106 The involvement of the dopaminergic system in the pathophysiology of dystonia has also been enhanced via the mutated genes of the dopamine pathway in monogenic forms of dystonia (GCH1).107 Allele 2 of the DRD5 has been associated with increased risk of CD and BSP in British cohorts.108,109 Allele 6 and allele 4 of the DRD5 have been associated with CD in British and Italian cohorts respectively,109,110 thus strongly supporting the involvement of the DRD5 gene in dystonia.111 However, DRD5 has not been associated with dystonia in Italian, US, and German studies.49,50 Dopamine receptor genes regulate neurotransmission in response to dopamine.112 Dopamine receptors are divided into two families, based on either the activation (D1-like receptors: DRD1 and DRD5) or the inhibition (D2-like receptors: DRD2, DRD3, and DRD4) of adenylate cyclase.113 Although the negative results in genes of dopamine signaling pathway (dopamine receptors) are few,49,114,115 Groen et al.115 suggested that changes in dopamine levels may be secondary during the dystonia course and that rare single nucleotide variants of dopamine genes are possibly associated with dystonia.116


To date, only two genome-wide association studies (GWASs) have been performed in order to identify variants that may predispose to dystonia.117,118 According to their results, there is a preliminary indication that arylsulfatase G (ARSG) and sodium leak channel (NALCN) variants play that role.117,118

In a GWAS executed by Lohmann et al.,117 it was suggested that the intronic rs11655081 (AF = 0.181) of the ARSG gene was associated with musician’s dystonia and writer’s cramp. The missense rs61999318 (AF = 0.002619) was significantly higher in the group of writer’s cramp patients than in European Americans in the EVS database (p = 0.0013).119 Functional analysis suggested that rs61999318 may represent a functional variant, as the underlying amino acid substitution of isoleucine at position 493 with threonine (p.I493T) appears to be disease causing.119 ARSG is the protein encoded by ARSG; it hydrolyzes sulfate esters and is therefore implicated in cell signaling, synthesis of hormones, and protein degradation.120 Moreover, it may be involved in neuronal ceroid lipofuscinosis,121 which can present itself as dystonia.117 In view of the former considerations, ARSG could be targeted as a gene for further study mainly in task-specific dystonias.

According to the GWAS from Mok et al.,118 the cluster of variants near exon 1 of NALCN was found nearest to the significance threshold in a British population with CD. The most statistically significant variants were NALCN (rs61973742, rs1338051, rs9518385, rs9518384, rs1338041 rs3916908), COL4A1 (rs619152), RGL1 (rs12132318), OR4X2 3 (rs67863238), intergenic (rs1249277, rs1249281, rs9416795), KIAA1715 (rs10930717), OR4B1 (rs35875350).118 However, a replication of this GWAS case–control study did not report any association of NALCN, OR4X2, COL4A1, and intergenic variants,122 and the results for NALC (rs1338041, rs61973742) were also not reproduced in a Chinese population.123 NALCN is a voltage-independent and cation-non-selective channel. Its main function is the leaky sodium transport across neuronal membranes and the regulation of neuronal excitability.124 In general, variants in genes, whose protein also acts like an ion channel, are crucial components and may be additional factors for dystonia development.117ANO3 is among the confirmed genes that cause a monogenic form of late-onset craniocervical dystonia, with a possible effect on the calcium-activated chloride channel.3,125

Concluding remarks

Genetic factors confer susceptibility to dystonia development. More precisely, based on our review, exon 4 and the 3′-UTR of exon 5 represent loci that appear to have a strong influence on the function of the TOR1A gene, and their pathogenic variants may be associated with sporadic forms of dystonia, specifically with focal distribution. Moreover, rs6265 of BDNF appears to be strongly associated with dystonia as well. As the function of the BDNF gene may be influenced by other variants, additional loci across it may be worth examining. Further analysis of the ARSG gene, notably the rs61999318 in focal task-specific dystonia cohorts and the DRD5 gene in focal dystonia, is warranted. Additional studies of GCH1 may be required. Owing to their rarity, THAP1 gene variants are insecure targets for future case–control studies. The continuing identification of pathogenic variants that cause monogenic forms of dystonia will lead us to new possible targets for case–control studies.1,3

Next-generation sequencing has led to the identification of new dystonia genes on a monthly basis.3,125,126 Therefore, a large amount of common and rare genetic variants that may predispose to dystonia have been identified. Also, a few identified variants may affect penetrance, age at onset, spread to adjacent body, or the phenotype of dystonia.15 However, it is not prudent to assume that all these genes truly lead to dystonia, and therefore results need to be interpreted with caution. Therefore, applying the CGASs approach to next-generation data could possibly shed some light on the mechanisms of the complex traits.127

The understanding of the genetic basis of monogenic and sporadic forms of dystonia will permit the identification and deeper knowledge of dystonia’s pathogenesis. This will provide physicians with more personalized tools to manage dystonia in the future, even from the time of diagnosis, and they may also be used for assessing the biological progression of the disease and guide the treatment decisions.128 Implications, even at the DNA and/or RNA level, are already considered as new possible targeted therapeutic approaches.53,80 The stronger grasp on dystonia’s genetic susceptibility will also improve genetic testing and counseling.

The lack of validation reproducibility of the positive results could be attributed to several factors; firstly, the culture of null hypothesis significance testing.77 Moreover, low power CGASs because of relatively small sample sizes is a common phenomenon, as the effective population should ideally be very large (∼10,000 individuals) in order for a modest genetic effect to be identified.129 The interplay between environmental (e.g. pesticides)86,98 and genetic factors, as well as among genetic factors,1 may variably determine the penetrance of pathogenic variants and the phenotype.18,20,86,98,130,131 Furthermore, the phenotypic divergence of dystonia and the possible classification bias should be considered, as the majority of the studies were performed before the new dystonia classification.4,15 Finally, epigenetic mechanisms may represent an additional explanation for the lack of result validation.78

Therefore, it is of great necessity that more collaborative studies132,133 with adjustment for other potential cofounders (e.g. gene–environment interactions with adjustment for pesticide exposure,86 air pollution,134 diseases of the anterior segment of the eye, preceded injury, trauma, surgical intervention or sore throat,130 time spent handwriting per day and the writing time before dystonia onset,135 genome methylation status) and a supportive functional analysis be conducted in the future. In this way, the pathogenic mechanisms of dystonia and the net effect of the genes could be elucidated and, consequently, the inherent limitations of association studies will be avoided.136

Certain limitations of the present review need to be acknowledged. Firstly, supportive data regarding functional analysis of variants would give more robustness to our conclusions. Moreover, we included relevant studies regardless of the sample power and without any prior quality assessment. Therefore, a possible confounding by population stratification or technical factors cannot totally be excluded. Finally, based on our search strategy procedure, it is possible that some eligible studies might not have been identified. However, this is an inherent limitation of such studies, and the inclusion of a large number of studies does not affect the major conclusions of our results.

We should bear in mind that positive results from genetic association studies require biological and functional evidence that the risk variant is actually involved in the pathophysiology and the pathogenesis of the relevant disease. Pathway-based analysis could facilitate more robust analysis even of GWAS and provide additional biological insights on the mechanisms of disease complex traits.137,138 Therefore, the scientific reasoning could not be replaced by any single statistical value, index, or test.105,139 As a consequence, by the correct interpretation of statistical values, the misinterpretation of results could be avoided.140


1 Funding: None. 

2 Financial Disclosures: None. 

3 Conflict of Interests: The authors report no conflict of interest. 

4 Ethics Statement: Not applicable for this category of article. 


  1. Balint, B and Valente, EM (2017). KMT2B: a new twist in dystonia genetics. Mov Disord 32: 529.DOI: [PubMed]  

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

  3. Lohmann, K and Klein, C (2017). Update on the genetics of dystonia. Curr Neurol Neurosci Rep 17: 26.DOI: [PubMed]  

  4. Albanese, A Bhatia, K Bressman, SB Delong, MR Fahn, S Fung, VS et al. (2013). Phenomenology and classification of dystonia: a consensus update. Mov Disord 28: 863–873, DOI: [PubMed]  

  5. Standaert, DG (2011). Update on the pathology of dystonia. Neurobiol Dis 42: 148–151, DOI: [PubMed]  

  6. Brookes, AJ (1999). The essence of SNPs. Gene 234: 177–186, DOI: [PubMed]  

  7. Kara, E Xiromerisiou, G Spanaki, C Bozi, M Koutsis, G Panas, M et al. (2014). Assessment of Parkinson’s disease risk loci in Greece. Neurobiol Aging 35: 442.e9–e16, DOI: 

  8. Dardiotis, E Fountas, KN Dardioti, M Xiromerisiou, G Kapsalaki, E Tasiou, A et al. (2010). Genetic association studies in patients with traumatic brain injury. Neurosurg Focus 28: E9.DOI: 

  9. Moraitou, M Hadjigeorgiou, G Monopolis, I Dardiotis, E Bozi, M Vassilatis, D et al. (2011). β-Glucocerebrosidase gene mutations in two cohorts of Greek patients with sporadic Parkinson's disease. Mol Genet Metab 104: 149–152, DOI: [PubMed]  

  10. Aerts, J, Wetzels, Y, Cohen, N and Aerssens, J (2002). Data mining of public SNP databases for the selection of intragenic SNPs. Hum Mutat 20: 162–173, DOI: [PubMed]  

  11. Xiromerisiou, G Kyratzi, E Dardiotis, E Bozi, M Tsimourtou, V Stamboulis, E et al. (2011). Lack of association of the UCHL-1 gene with Parkinson’s disease in a Greek cohort: a haplotype-tagging approach. Mov Disord 26: 1955–1957, DOI: [PubMed]  

  12. Lee, EK and Gorospe, M (2011). Coding region: the neglected post-transcriptional code. RNA Biol 8: 44–48, DOI: [PubMed]  

  13. Hoskinson, DC, Dubuc, AM and Mason-Suares, H (2017). The current state of clinical interpretation of sequence variants. Curr Opin Genet Dev 42: 33–39, DOI: [PubMed]  

  14. Richards, S Aziz, N Bale, S Bick, D Das, S Gastier-Foster, J et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17: 405–424, DOI: [PubMed]  

  15. Siokas, V Dardiotis, E Tsironi, EE Tsivgoulis, G Rikos, D Sokratous, M et al. (2017). The role of TOR1A polymorphisms in dystonia: a systematic review and meta-analysis. PloS one 12: e0169934.DOI: [PubMed]  

  16. Balint, B and Bhatia, KP (2015). Isolated and combined dystonia syndromes – an update on new genes and their phenotypes. Eur J Neurol 22: 610–617, DOI: [PubMed]  

  17. Camargo, CH, Camargos, ST, Cardoso, FE and Teive, HA (2015). The genetics of the dystonias—a review based on the new classification of the dystonias. Arqu Neuro-psiquiatr 73: 350–358.  

  18. Charlesworth, G, Bhatia, KP and Wood, NW (2013). The genetics of dystonia: new twists in an old tale. Brain 136((Pt 7)): 2017–2037, DOI: [PubMed]  

  19. Xiao, J, Vemula, SR and LeDoux, MS (2014). Recent advances in the genetics of dystonia. Curr Neurol Neurosci Rep 14: 462.DOI: [PubMed]  

  20. Petrucci, S and Valente, EM (2013). Genetic issues in the diagnosis of dystonias. Front Neurol 4: 34.DOI: [PubMed]  

  21. LeDoux, MS (2012). The genetics of dystonias. Adv Genet 79: 35–85, DOI: [PubMed]  

  22. Phukan, J, Albanese, A, Gasser, T and Warner, T (2011). Primary dystonia and dystonia-plus syndromes: clinical characteristics, diagnosis, and pathogenesis. Lancet Neurol 10: 1074–1085, DOI: [PubMed]  

  23. Fung, VS, Jinnah, HA, Bhatia, K and Vidailhet, M (2013). Assessment of patients with isolated or combined dystonia: an update on dystonia syndromes. Mov Disord 28: 889–898, DOI: [PubMed]  

  24. Klein, C (2014). Genetics in dystonia. Parkinsonism Relat Disord 20(Suppl. 1): S137–142, DOI: [PubMed]  

  25. Lohmann, K and Klein, C (2013). Genetics of dystonia: what’s known? What’s new? What’s next?. Mov Disord 28: 899–905, DOI: [PubMed]  

  26. Marras, C Lang, A van de Warrenburg, BP Sue, CM Tabrizi, SJ Bertram, L et al. (2016). Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord 31: 436–457, DOI: [PubMed]  

  27. Ozelius, LJ Hewett, JW Page, CE Bressman, SB Kramer, PL Shalish, C et al. (1997). The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 17: 40–8, DOI: [PubMed]  

  28. Goodchild, RE and Dauer, WT (2004). Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc Natl Acad Sci USA 101: 847–852, DOI: [PubMed]  

  29. Grillet, M Dominguez Gonzalez, B Sicart, A Pottler, M Cascalho, A Billion, K et al. (2016). Torsins are essential regulators of cellular lipid metabolism. Dev Cell 38: 235–247, DOI: [PubMed]  

  30. Cascalho, A, Jacquemyn, J and Goodchild, RE (2017). Membrane defects and genetic redundancy: are we at a turning point for DYT1 dystonia?. Mov Disord 32: 371–381, DOI: [PubMed]  

  31. Hettich, J Ryan, SD de Souza, ON Saraiva Macedo Timmers, LF Tsai, S Atai, NA et al. (2014). Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A. Hum Mutat 35: 1101–1113, DOI: [PubMed]  

  32. Sosa, BA, Demircioglu, FE, Chen, JZ, Ingram, J, Ploegh, HL and Schwartz, TU (2014). How lamina-associated polypeptide 1 (LAP1) activates Torsin. eLife 3: e03239.DOI: [PubMed]  

  33. Demircioglu, FE, Sosa, BA, Ingram, J, Ploegh, HL and Schwartz, TU (2016). Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. eLife 5DOI: 

  34. Naismith, TV, Dalal, S and Hanson, PI (2009). Interaction of torsinA with its major binding partners is impaired by the dystonia-associated DeltaGAG deletion. J Biol Chem 284: 27866–278664, DOI: [PubMed]  

  35. Wang, L Duan, C Gao, Y Xu, W Ding, J Liu, VT et al. (2016). Lack of association between TOR1A and THAP1 mutations and sporadic adult-onset primary focal dystonia in a Chinese population. Clin Neurol Neurosurg 142: 26–30, DOI: [PubMed]  

  36. Zhou, Q Chen, Y Yang, J Cao, B Wei, Q Ou, R et al. (2016). Association analysis of TOR1A polymorphisms rs2296793 and rs3842225 in a Chinese population with cervical dystonia. Neurosci Lett 612: 185–188, DOI: [PubMed]  

  37. Timerbaeva, SL, Abramycheva, NY, Rebrova, OY and Illarioshkin, SN (2015). TOR1A polymorphisms in a Russian cohort with primary focal/segmental dystonia. Int J Neurosci 125: 671–677, DOI: [PubMed]  

  38. Caputo, M Irisarri, M Perandones, C Alechine, E Pellene, LA Roca, CU et al. (2013). Analysis of D216H polymorphism in Argentinean patients with primary dystonia. J Neurogenet 27: 16–18, DOI: [PubMed]  

  39. Groen, JL Ritz, K Tanck, MW van de Warrenburg, BP van Hilten, JJ Aramideh, M et al. (2013). Is TOR1A a risk factor in adult-onset primary torsion dystonia?. Mov Disord 28: 827–831, DOI: [PubMed]  

  40. Newman, JR Sutherland, GT Boyle, RS Limberg, N Blum, S O'Sullivan, JD et al. (2012). Common polymorphisms in dystonia-linked genes and susceptibility to the sporadic primary dystonias. Parkinsonism Relat Disord 18: 351–357, DOI: [PubMed]  

  41. Chen, Y Chen, K Burgunder, JM Song, W Huang, R Zhao, B et al. (2012). Association of rs1182 polymorphism of the DYT1 gene with primary dystonia in Chinese population. J Neurolog Sci 323: 228–231, DOI: 

  42. Chen, Y, Burgunder, JM, Song, W, Huang, R and Shang, HF (2012). Assessment of D216H DYT1 polymorphism in a Chinese primary dystonia patient cohort. Eur J Neurol 19: 924–926, DOI: [PubMed]  

  43. Sharma, N Franco, RA Jr Kuster, JK Mitchell, AA Fuchs, T Saunders-Pullman, R et al. (2010). Genetic evidence for an association of the TOR1A locus with segmental/focal dystonia. Mov Disord 25: 2183–2187, DOI: [PubMed]  

  44. Bruggemann, N Kock, N Lohmann, K Konig, IR Rakovic, A Hagenah, J et al. (2009). The D216H variant in the DYT1 gene: a susceptibility factor for dystonia in familial cases?. Neurology 72: 1441–1443, DOI: [PubMed]  

  45. Cheng, FB Wan, XH Zhang, Y Miao, J Sun, Y Sun, YB et al. (2013). TOR1A sequence variants and the association with early-onset primary dystonia in the Chinese Han population. Parkinsonism Relat Disord 19: 399–401, DOI: [PubMed]  

  46. Kamm, C Asmus, F Mueller, J Mayer, P Sharma, M Muller, UJ et al. (2006). Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia. Neurology 67: 1857–1859, DOI: [PubMed]  

  47. Naiya, T Biswas, A Neogi, R Datta, S Misra, AK Das, SK et al. (2006). Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta Neurolog Scand 114: 210–215, DOI: 

  48. Clarimon, J Asgeirsson, H Singleton, A Jakobsson, F Hjaltason, H Hardy, J et al. (2005). Torsin A haplotype predisposes to idiopathic dystonia. Ann Neurol 57: 765–767, DOI: [PubMed]  

  49. Clarimon, J Brancati, F Peckham, E Valente, EM Dallapiccola, B Abruzzese, G et al. (2007). Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm. Mov Disord 22: 162–166, DOI: [PubMed]  

  50. Sibbing, D Asmus, F Konig, IR Tezenas du Montcel, S Vidailhet, M Sangla, S et al. (2003). Candidate gene studies in focal dystonia. Neurology 61: 1097–1101, DOI: [PubMed]  

  51. Hague, S Klaffke, S Clarimon, J Hemmer, B Singleton, A Kupsch, A et al. (2006). Lack of association with TorsinA haplotype in German patients with sporadic dystonia. Neurology 66: 951–952, DOI: [PubMed]  

  52. Li, J Long, Y Huang, X Chen, Y Chen, W Liu, S et al. (2017). Deletion variant rs35153737 in TOR1A is associated with isolated dystonia in a southwestern Chinese population. Neurosci Lett 657: 1–4, DOI: [PubMed]  

  53. Long, Y Chen, Y Qian, Y Wang, J Luo, L Huang, X et al. (2017). A rare variant in TOR1A exon 5 associated with isolated dystonia in southwestern Chinese. Mov Disord 32: 1083–1087, DOI: [PubMed]  

  54. Kamm, C Fischer, H Garavaglia, B Kullmann, S Sharma, M Schrader, C et al. (2008). Susceptibility to DYT1 dystonia in European patients is modified by the D216H polymorphism. Neurology 70: 2261–2262, DOI: [PubMed]  

  55. Risch, NJ, Bressman, SB, Senthil, G and Ozelius, LJ (2007). Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. Am J Hum Genet 80: 1188–93, DOI: [PubMed]  

  56. Kojovic, M Parees, I Kassavetis, P Palomar, FJ Mir, P Teo, JT et al. (2013). Secondary and primary dystonia: pathophysiological differences. Brain 136((Pt 7)): 2038–2049, DOI: [PubMed]  

  57. Quartarone, A Morgante, F Sant’angelo, A Rizzo, V Bagnato, S Terranova, C et al. (2008). Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia. J Neurol Neurosurg Psychiatry 79: 985–990, DOI: [PubMed]  

  58. Martino, D Muglia, M Abbruzzese, G Berardelli, A Girlanda, P Liguori, M et al. (2009). Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia. Eur J Neurol 16: 949–952, DOI: [PubMed]  

  59. Hempstead, BL (2015). Brain-derived neurotrophic factor: three ligands, many actions. Trans Am Clin Climatol Assoc 126: 9–19. [PubMed]  

  60. Notaras, M, Hill, R and van den Buuse, M (2015). The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry 20: 916–930, DOI: [PubMed]  

  61. Anastasia, A and Hempstead, BL (2014). BDNF function in health and disease (Poster). Nat Rev Neurosci 15 doi: 

  62. Cheeran, B Talelli, P Mori, F Koch, G Suppa, A Edwards, M et al. (2008). A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 586: 5717–5725, DOI: [PubMed]  

  63. Kleim, JA Chan, S Pringle, E Schallert, K Procaccio, V Jimenez, R et al. (2006). BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci 9: 735–737, DOI: [PubMed]  

  64. Chen, J, Liang, X, Li, B, Jiang, X and Xu, Z (2014). Gender-related association of brain-derived neurotrophic factor gene 196A/G polymorphism with Alzheimer’s disease—a meta-analysis including 6854 cases and 6868 controls. Int J Neurosci 124: 724–733, DOI: [PubMed]  

  65. Chen, K Wang, N Zhang, J Hong, X Xu, H Zhao, X et al. (2017). Is the Val66Met polymorphism of the brain-derived neurotrophic factor gene associated with panic disorder? A meta-analysis. Asia-Pacific Psychiatry 9DOI: 

  66. Zintzaras, E (2007). Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis. Psychiatric Genet 17: 69–75, DOI: 

  67. Zintzaras, E and Hadjigeorgiou, GM (2005). The role of G196A polymorphism in the brain-derived neurotrophic factor gene in the cause of Parkinson’s disease: a meta-analysis. J Hum Genet 50: 560–566, DOI: [PubMed]  

  68. Li, M, Chang, H and Xiao, X (2016). BDNF Val66Met polymorphism and bipolar disorder in European populations: a risk association in case-control, family-based and GWAS studies. Neurosci Biobehav Rev 68: 218–233, DOI: [PubMed]  

  69. Xiromerisiou, G Dardiotis, E Tsimourtou, V Kountra, PM Paterakis, KN Kapsalaki, EZ et al. (2010). Genetic basis of Parkinson disease. Neurosurg Focus 28: E7.DOI: 

  70. Chen, Y Song, W Yang, J Chen, K Huang, R Zhao, B et al. (2013). Association of the Val66Met polymorphism of the BDNF gene with primary cranial-cervical dystonia patients from South-west China. Parkinsonism Relat Disord 19: 1043–1045, DOI: [PubMed]  

  71. Cramer, SC, Sampat, A, Haske-Palomino, M, Nguyen, S, Procaccio, V and Hermanowicz, N (2010). Increased prevalence of val(66)met BDNF genotype among subjects with cervical dystonia. Neurosci Lett 468: 42–45, DOI: [PubMed]  

  72. Groen, JL Ritz, K Velseboer, DC Aramideh, M van Hilten, JJ Boon, AJ et al. (2012). Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia. Mov Disord 27: 796–797, DOI: [PubMed]  

  73. Ma, L Chen, Y Wang, L Yang, Y Cheng, F Tian, Y et al. (2013). Brain-derived neurotrophic factor Val66Met polymorphism is not associated with primary dystonia in a Chinese population. Neurosci Lett 533: 100–103, DOI: [PubMed]  

  74. Svetel, MV Djuric, G Novakovic, I Dobricic, V Stefanova, E Kresojevic, N et al. (2013). A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia. Acta Neurolog Belg 113: 243–245, DOI: 

  75. Gomez-Garre, P Huertas-Fernandez, I Caceres-Redondo, MT Alonso-Canovas, A Bernal-Bernal, I Blanco-Ollero, A et al. (2014). BDNF Val66Met polymorphism in primary adult-onset dystonia: a case-control study and meta-analysis. Mov Disord 29: 1083–1086, DOI: [PubMed]  

  76. Sako, W, Murakami, N, Izumi, Y and Kaji, R (2015). Val66Met polymorphism of brain-derived neurotrophic factor is associated with idiopathic dystonia. J Clin Neurosci 22: 575–577, DOI: [PubMed]  

  77. Lash, TL (2017). The harm done to reproducibility by the culture of null hypothesis significance testing. Am J Epidemiol 186: 627–635, DOI: [PubMed]  

  78. Ikegame, T, Bundo, M, Murata, Y, Kasai, K, Kato, T and Iwamoto, K (2013). DNA methylation of the BDNF gene and its relevance to psychiatric disorders. J Hum Genet 58: 434–438, DOI: [PubMed]  

  79. Terracciano, A Piras, MG Lobina, M Mulas, A Meirelles, O Sutin, AR et al. (2013). Genetics of serum BDNF: meta-analysis of the Val66Met and genome-wide association study. World J Biolog Psychiatry 14: 583–589, DOI: 

  80. Nagahara, AH and Tuszynski, MH (2011). Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10: 209–219, DOI: [PubMed]  

  81. Longo, FM and Massa, SM (2013). Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov 12: 507–525, DOI: [PubMed]  

  82. Deng, P, Anderson, JD, Yu, AS, Annett, G, Fink, KD and Nolta, JA (2016). Engineered BDNF producing cells as a potential treatment for neurologic disease. Expert Opin Biol Ther 16: 1025–1033, DOI: [PubMed]  

  83. Mahley, RW and Rall, SC Jr (2000). Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1: 507–537, DOI: [PubMed]  

  84. Liu, CC, Liu, CC, Kanekiyo, T, Xu, H and Bu, G (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9: 106–118, DOI: [PubMed]  

  85. Matsumoto, S Nishimura, M Sakamoto, T Asanuma, K Izumi, Y Shibasaki, H et al. (2003). Modulation of the onset age in primary dystonia by APOE genotype. Neurology 60: 2003–2005, DOI: [PubMed]  

  86. Xiromerisiou, G Dardiotis, E Tsironi, EE Hadjigeorgiou, G Ralli, S Kara, E et al. (2013). THAP1 mutations in a Greek primary blepharospasm series. Parkinsonism Relat Disord 19: 404–405, DOI: [PubMed]  

  87. Xiromerisiou, G Houlden, H Scarmeas, N Stamelou, M Kara, E Hardy, J et al. (2012). THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. Mov Disord 27: 1290–1294, DOI: [PubMed]  

  88. Blanchard, A Ea, V Roubertie, A Martin, M Coquart, C Claustres, M et al. (2011). DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. Hum Mutat 32: 1213–1224, DOI: [PubMed]  

  89. Gavarini, S Cayrol, C Fuchs, T Lyons, N Ehrlich, ME Girard, JP et al. (2010). Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann Neurol 68: 549–553, DOI: [PubMed]  

  90. Houlden, H Schneider, SA Paudel, R Melchers, A Schwingenschuh, P Edwards, M et al. (2010). THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 74: 846–850, DOI: [PubMed]  

  91. Groen, JL Yildirim, E Ritz, K Baas, F van Hilten, JJ van der Meulen, FW et al. (2011). THAP1 mutations are infrequent in spasmodic dysphonia. Mov Disord 26: 1952–1954, DOI: [PubMed]  

  92. Golanska, E Gajos, A Sieruta, M Szybka, M Rudzinska, M Ochudlo, S et al. (2015). Screening for THAP1 mutations in Polish patients with dystonia shows known and novel substitutions. PloS one 10: e0129656.DOI: [PubMed]  

  93. Xiao, J Zhao, Y Bastian, RW Perlmutter, JS Racette, BA Tabbal, SD et al. (2010). Novel THAP1 sequence variants in primary dystonia. Neurology 74: 229–238, DOI: [PubMed]  

  94. Djarmati, A Schneider, SA Lohmann, K Winkler, S Pawlack, H Hagenah, J et al. (2009). Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol 8: 447–452, DOI: [PubMed]  

  95. Giri, S Naiya, T Equbal, Z Sankhla, CS Das, SK Ray, K et al. (2017). Genetic screening of THAP1 in primary dystonia patients of India. Neurosci Lett 637: 31–37, DOI: [PubMed]  

  96. Vemula, SR Xiao, J Zhao, Y Bastian, RW Perlmutter, JS Racette, BA et al. (2014). A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia. Mol genet genom med 2: 261–272, DOI: 

  97. Xiao, J Zhao, Y Bastian, RW Perlmutter, JS Racette, BA Tabbal, SD et al. (2011). The c.-237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia. Mov Disord 26: 549–552, DOI: [PubMed]  

  98. Dardiotis, E, Xiromerisiou, G, Hadjichristodoulou, C, Tsatsakis, AM, Wilks, MF and Hadjigeorgiou, GM (2013). The interplay between environmental and genetic factors in Parkinson's disease susceptibility: the evidence for pesticides. Toxicology 307: 17–23, DOI: [PubMed]  

  99. Fuchs, T Saunders-Pullman, R Masuho, I Luciano, MS Raymond, D Factor, S et al. (2013). Mutations in GNAL cause primary torsion dystonia. Nat Genet 45: 88–92, DOI: [PubMed]  

  100. Miao, J, Wan, XH, Sun, Y, Feng, JC and Cheng, FB (2013). Mutation screening of GNAL gene in patients with primary dystonia from Northeast China. Parkinsonism Relat Disord 19: 910–912, DOI: [PubMed]  

  101. Carapito, R Paul, N Untrau, M Le Gentil, M Ott, L Alsaleh, G et al. (2015). A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia. Mov Disord 30: 423–427, DOI: [PubMed]  

  102. Newman, JR, Todorovic, M, Silburn, PA, Sutherland, GT and Mellick, GD (2014). Lack of reproducibility in re-evaluating associations between GCH1 polymorphisms and Parkinson's disease and isolated dystonia in an Australian case—control group. Parkinsonism Relat Disord 20(6): 668–70, DOI: [PubMed]  

  103. Opladen, T Hoffmann, G Horster, F Hinz, AB Neidhardt, K Klein, C et al. (2011). Clinical and biochemical characterization of patients with early infantile onset of autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia. Mov Disord 26: 157–161, DOI: [PubMed]  

  104. Hwu, WL, Chiou, YW, Lai, SY and Lee, YM (2000). Dopa-responsive dystonia is induced by a dominant-negative mechanism. Ann Neurol 48: 609–613, DOI:>3.0.CO;2-H [PubMed]  

  105. Rothman, KJ (2016). Disengaging from statistical significance. Eur J Epidemiol 31: 443–444, DOI: [PubMed]  

  106. Tanabe, LM, Kim, CE, Alagem, N and Dauer, WT (2009). Primary dystonia: molecules and mechanisms. Nat Rev Neurol 5: 598–609, DOI: [PubMed]  

  107. Ichinose, H Ohye, T Takahashi, E Seki, N Hori, T Segawa, M et al. (1994). Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 8: 236–242, DOI: [PubMed]  

  108. Misbahuddin, A, Placzek, MR, Chaudhuri, KR, Wood, NW, Bhatia, KP and Warner, TT (2002). A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm. Neurology 58: 124–126, DOI: [PubMed]  

  109. Placzek, MR, Misbahuddin, A, Chaudhuri, KR, Wood, NW, Bhatia, KP and Warner, TT (2001). Cervical dystonia is associated with a polymorphism in the dopamine (D5) receptor gene. J Neurol Neurosurg Psychiatry 71: 262–264, DOI: [PubMed]  

  110. Brancati, F Valente, EM Castori, M Vanacore, N Sessa, M Galardi, G et al. (2003). Role of the dopamine D5 receptor (DRD5) as a susceptibility gene for cervical dystonia. J Neurol Neurosurg Psychiatry 74: 665–666, DOI: [PubMed]  

  111. Misbahuddin, A, Placzek, MR and Warner, TT (2004). Focal dystonia is associated with a polymorphism of the dopamine D5 receptor gene. Adv Neurol 94: 143–146. [PubMed]  

  112. Housley, DJ Nikolas, M Venta, PJ Jernigan, KA Waldman, ID Nigg, JT et al. (2009). SNP discovery and haplotype analysis in the segmentally duplicated DRD5 coding region. Ann Hum Genet 73((Pt 3)): 274–282, DOI: [PubMed]  

  113. Gingrich, JA and Caron, MG (1993). Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci 16: 299–321, DOI: [PubMed]  

  114. Zeuner, KE, Acewicz, A, Knutzen, A, Dressler, D, Lohmann, K and Witt, K (2016). Dopamine DRD2 polymorphism (DRD2/ANNK1-Taq1A) is not a significant risk factor in writer’s cramp. J Neurogenet 30: 276–279, DOI: [PubMed]  

  115. Groen, JL Simon-Sanchez, J Ritz, K Bochdanovits, Z Fang, Y van Hilten, JJ et al. (2013). Cervical dystonia and genetic common variation in the dopamine pathway. Parkinsonism Relat Disord 19: 346–349, DOI: [PubMed]  

  116. Groen, JL, Ritz, K, Warner, TT, Baas, F and Tijssen, MA (2014). DRD1 rare variants associated with tardive-like dystonia: a pilot pathway sequencing study in dystonia. Parkinsonism Relat Disord 20: 782–785, DOI: [PubMed]  

  117. Lohmann, K Schmidt, A Schillert, A Winkler, S Albanese, A Baas, F et al. (2014). Genome-wide association study in musician’s dystonia: a risk variant at the arylsulfatase G locus?. Mov Disord 29: 921–927, DOI: [PubMed]  

  118. Mok, KY Schneider, SA Trabzuni, D Stamelou, M Edwards, M Kasperaviciute, D et al. (2014). Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel. Mov Disord 29: 245–251, DOI: [PubMed]  

  119. Nibbeling, E Schaake, S Tijssen, MA Weissbach, A Groen, JL Altenmuller, E et al. (2015). Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia. J Neurol 262: 1340–1343, DOI: [PubMed]  

  120. Sardiello, M, Annunziata, I, Roma, G and Ballabio, A (2005). Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship. Hum Mol Genet 14: 3203–3217, DOI: [PubMed]  

  121. Abitbol, M Thibaud, JL Olby, NJ Hitte, C Puech, JP Maurer, M et al. (2010). A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci USA 107: 14775–14780, DOI: [PubMed]  

  122. Gomez-Garre, P Huertas-Fernandez, I Caceres-Redondo, MT Alonso-Canovas, A Bernal-Bernal, I Blanco-Ollero, A et al. (2014). Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study. Mov Disord 29: 1825–1828, DOI: [PubMed]  

  123. Zhou, Q Yang, J Cao, B Chen, Y Wei, Q Ou, R et al. (2016). Association analysis of NALCN polymorphisms rs1338041 and rs61973742 in a Chinese population with isolated cervical dystonia. Parkinsons Dis 2016: 9281790.DOI: [PubMed]  

  124. Topalidou, I, Cooper, K, Pereira, L and Ailion, M (2017). Dopamine negatively modulates the NCA ion channels in C. elegans. PLoS Genet 13: e1007032.DOI: [PubMed]  

  125. Domingo, A, Erro, R and Lohmann, K (2016). Novel dystonia genes: clues on disease mechanisms and the complexities of high-throughput sequencing. Mov Disord 31: 471–477, DOI: [PubMed]  

  126. Coughlin, DG, Bardakjian, TM, Spindler, M and Deik, A (2018). Hereditary myoclonus dystonia: a novel sgce variant and phenotype including intellectual disability. Tremor Other Hyperkinet Mov 8DOI: 

  127. Patnala, R, Clements, J and Batra, J (2013). Candidate gene association studies: a comprehensive guide to useful in silico tools. BMC Genet 14: 39.DOI: [PubMed]  

  128. Oterdoom, DLM van Egmond, ME Ascencao, LC van Dijk, JMC Saryyeva, A Beudel, M et al. (2018). Reversal of status dystonicus after relocation of pallidal electrodes in DYT6 generalized dystonia. Tremor Other Hyperkinet Mov 8 

  129. Zintzaras, E and Lau, J (2008). Trends in meta-analysis of genetic association studies. J Hum Genet 53: 1–9, DOI: [PubMed]  

  130. Defazio, G, Berardelli, A and Hallett, M (2007). Do primary adult-onset focal dystonias share aetiological factors?. Brain 130((Pt 5)): 1183–1193, DOI: [PubMed]  

  131. Defazio, G Matarin, M Peckham, EL Martino, D Valente, EM Singleton, A et al. (2009). The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm. Mov Disord 24: 613–616, DOI: [PubMed]  

  132. Evangelou, E Maraganore, DM Annesi, G Brighina, L Brice, A Elbaz, A et al. (2010). Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson’s disease: large-scale collaborative study. Am J Med Genet B Neuropsychiatr Genet 153b: 220–8, DOI: [PubMed]  

  133. Theuns, J Verstraeten, A Sleegers, K Wauters, E Gijselinck, I Smolders, S et al. (2014). Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83: 1906–1913, DOI: [PubMed]  

  134. The Lancet, N (2018). Air pollution and brain health: an emerging issue. Lancet Neurol 17: 103.DOI: [PubMed]  

  135. Vidailhet, M, Grabli, D and Roze, E (2009). Pathophysiology of dystonia. Curr Opin Neurol 22: 406–413, DOI: [PubMed]  

  136. Cardon, LR and Bell, JI (2001). Association study designs for complex diseases. Nat Rev Genet 2: 91–99, DOI: [PubMed]  

  137. Wang, K, Li, M and Hakonarson, H (2010). Analysing biological pathways in genome-wide association studies. Nat Rev Genet 11: 843–854, DOI: [PubMed]  

  138. Li, Y Rowland, C Xiromerisiou, G Lagier, RJ Schrodi, SJ Dradiotis, E et al. (2008). Neither replication nor simulation supports a role for the axon guidance pathway in the genetics of Parkinson's disease. PloS one 3: e2707.DOI: [PubMed]  

  139. Wasserstein, RL and Lazar, NA (2016). The ASA’s statement on p-values: context, process, and purpose. Am Stat 70: 129–33, DOI: 

  140. Greenland, S (2017). Invited commentary: the need for cognitive science in methodology. Am J Epidemiol 186: 639–645, DOI: [PubMed]  

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