Common polymorphisms in dystonia-linked genes and susceptibility to the sporadic primary dystonias
Introduction
Primary dystonia is a group of related movement disorders characterised by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. This is thought to arise from a dysfunction of the central neural circuits that control and coordinate voluntary movements, such as those found in the basal ganglia [1], the cerebellum [2], the sensorimotor cortex [3], and the interactions between these three regions of the brain [4]. While the rare early-onset forms of dystonia can sometimes be traced to inherited genetic abnormalities, the more common late-onset forms arise sporadically with no clear aetiology [1]. It has been postulated that the sporadic forms of primary dystonia are caused by an interaction between genetic and non-genetic factors [5]. Sporadic primary dystonia is comprised of multiple phenotypic subtypes, classified by bodily presentation and distribution. However, the prevalence of primary dystonia is relatively low in the general population with the average European prevalence estimated at 152 cases per million and the estimated prevalence of each subtype substantially lower [6]. While there may be subtype-specific risk factors [7], [8], [9], there may also be susceptibility factors that are common to all sporadic primary dystonias. Given that the different subtypes can co-present in individual patients (concurrently at onset or sequentially) and that many seem to share neurophysiological similarities [5], it seems valid to group these subtypes into a single phenotype to identify such shared risk factors. The purpose of this study is to identify shared genetic risk factors for the sporadic primary dystonias.
To date there have been at least 17 genetic loci linked to familial forms of dystonia. At eight of these loci, causative mutations have been found in so-called DYT genes. These mutations cause rare and usually early-onset forms of familial dystonia or “dystonia plus” syndromes, including torsion dystonia (for example, DYT1, DYT6), myoclonus dystonia (DYT11), dystonia-parkinsonism (DYT3, DYT12, DYT16), paroxysmal/episodic dyskensia (DYT8) and dopa-responsive dystonia (DYT5) (for background information regarding these dystonia syndromes, please refer to Supplementary References). While these disorders display a rather disparate phenotypic spectrum dystonia is often prominent in these disorders, if not the only presenting symptom [10], [11]. It is therefore an attractive option to investigate these genes as candidates for sporadic primary dystonia. This approach to candidate susceptibility loci has been employed with some success for other neurological diseases which have known genetic causes in a small proportion of cases; good examples include Parkinson’s disease [12] and Alzheimer’s disease [13].
To date there have been few published candidate genes association studies examining sporadic primary dystonia, and only two of the known DYT genes, TOR1A (DYT1) and THAP1 (DYT6), have been studied. Six candidate genes studies have examined common single nucleotide polymorphisms (SNPs) in and around the TOR1A gene. Two of these studies showed strong associations between individual SNPs and susceptibility for primary dystonia in populations from Iceland [14], southern Germany and Austria [15], and the United States [16]. Others have shown modest associations in Indian, Italian and northern German populations [7], [8], [17]. However, other similar studies have not replicated these findings [8], [18], [19]. In contrast to TOR1A, no strong associations have been reported with polymorphisms in the THAP1 gene [20], [21], although rare variants within the THAP1 coding regions may be a cause of some adult-onset cases [22].
Here we look to extend the previous studies by testing the hypothesis that common SNPs in various DYT genes influence the susceptibility to sporadic primary dystonia in a well-characterised Australian case–control sample. First, we used a similar haplotype-tagging approach to that of Kamm et al. [15] to cover the common genetic variability in TOR1A followed by a meta-analysis of four previously studied TOR1A SNPs. We then applied haplotype-tagging approaches to investigate seven other DYT genes: TAF1 (DYT3), GCH1 (DYT5), THAP1 (DYT6), MR-1 (DYT8, also known as PNKD), SGCE (DYT11), ATP1A3 (DYT12) and PRKRA (DYT16).
Section snippets
Case ascertainment
Subjects were recruited from neurology clinics in Brisbane, Australia between 2003 and 2011. Diagnosis of sporadic primary dystonia was made by an experienced movement disorder specialist using standard diagnostic criteria. Cases were defined as “sporadic” if they were negative for the TOR1A ΔE302/303 mutation and either had an onset age greater than 30 years, or reported no family history of dystonia or dystonia plus syndromes at time of recruitment. Patients with focal, segmental, multifocal
Tagging SNP selection
Forty-six tagging SNPs were selected from HapMap data and published literature. Since no HapMap SNPs around the THAP1 gene met our tagging SNP selection criteria, we included three previously identified polymorphisms (c.-237_-236GA>TT, c.71+9C>A, c.71+126T>C). To further characterise the common variation in the THAP1 genomic region, we complemented these variants with six SNPs identified in CEU individuals (minor allele frequency > 4%) as a part of the 1000 Genomes Project. In addition, one of
Discussion
Mutations in the TOR1A, TAF1, GCH1, THAP1, MR-1 (PNKD), SGCE, ATP1A3 and PRKRA genes have all been previously linked with familial dystonia syndromes. As associations between common variants in TOR1A and THAP1 and sporadic dystonia have been previously reported, it seemed reasonable to extend a candidate gene approach to all eight genes. There are other DYT genes such as SLC2A1 (DYT18) which could have been investigated as interesting candidates in this project for association with primary
Financial disclosures/conflict of interest
The authors disclose no conflict of interest.
Acknowledgements
We would like to thank Gerhard Siebert, Nadeeka Dissanayaka, Sarah Day, Coral Gartner, Madeline Minslow and Karen O’Maley for expert assistance, Sullivan and Nicolaides Pathology for assistance with blood collection, and Brett Chapman, Jennifer Templeton and Tamara Macdonald for assistance with SNP genotyping design and implementation. Financial support for this project was obtained from internal funding for G. D. Mellick.
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Association of GCH1 and MIR4697, but not SIPA1L2 and VPS13C polymorphisms, with Parkinson's disease in Taiwan
2016, Neurobiology of AgingCitation Excerpt :Functional GCH1 haplotype comprised rs8007267-rs3783641-rs10483639 has been shown to affect the expression of GCH1 (Tegeder et al., 2006). A modest association of rs10483639 was seen in the original case-control series of 226 PD cases and 228 age- and gender-matched controls, whereas it was not found in a subsequent larger Australian case-control group (Newman et al., 2012, 2014). It is notable that GCH1 rs11158026 and rs7155501 were not examined in the Australian group.
Lack of association between TOR1A and THAP1 mutations and sporadic adult-onset primary focal dystonia in a Chinese population
2016, Clinical Neurology and NeurosurgeryAssociation analysis of TOR1A polymorphisms rs2296793 and rs3842225 in a Chinese population with cervical dystonia
2016, Neuroscience LettersCitation Excerpt :However, a study from southern Germany and Austria observed a strong protective effect by the same haplotype, although each single polymorphism did not separately show a protective effect [16]. Moreover, two meta-analyses on the TOR1A SNPs revealed a lack of association between the two SNPs (rs2296793 and rs3842225) and dystonia [13,14]. No studies on the association between the two SNPs and dystonia in a Chinese population were available.
Val66Met polymorphism of brain-derived neurotrophic factor is associated with idiopathic dystonia
2015, Journal of Clinical NeuroscienceCitation Excerpt :The direct comparison between dystonia with and without Val66Met polymorphism could provide insights into the underlying pathomechanism of dystonia using BDNF concentration in the blood and/or cerebrospinal fluid, electrophysiology and neuroimaging. Meta-analyses were applied to estimate the effect of several SNP of dystonia-related genes on idiopathic dystonia, however, they revealed only one association of SNP of TOR1A (NCBI rs1801968) with familial dystonia [22,23]. The analysis of gene-gene interaction could help to identify higher-risk combinations of SNPs although a single polymorphism does not seem involved in dystonia.