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Research paper
Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis
  1. Eduardo Preusser de Mattos1,2,3,
  2. Maiara Kolbe Musskopf2,
  3. Vanessa Bielefeldt Leotti4,5,
  4. Maria Luiza Saraiva-Pereira1,2,6,7,
  5. Laura Bannach Jardim1,2,7,8
  1. 1 Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  2. 2 Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
  3. 3 Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen/Groningen University, Groningen, The Netherlands
  4. 4 Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  5. 5 Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  6. 6 Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  7. 7 Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
  8. 8 Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  1. Correspondence to Dr Laura Bannach Jardim, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rua Ramiro Barcelos 2350, Brazil; ljardim{at}hcpa.edu.br

Abstract

Objectives To perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD).

Methods Two authors independently reviewed reports on the mathematical relationship between CAG length at the expanded ATXN3 allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071).

Results Eleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate ATXN2 alleles (27–33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at ATXN2 together explained 73.5% of AO variance.

Conclusions Current evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, ATXN2 and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance.

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Introduction

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a neurological condition characterised by expansion of a polymorphic trinucleotide CAG tract (CAGexp) at ATXN3. SCA3/MJD is the most common dominantly inherited ataxia worldwide,1 2 and ATXN3 alleles with ≥45 repeats code for ataxin-3 proteins with abnormally long polyglutamine (polyQ) sequences. PolyQ-expanded ataxin-3 is prone to aggregation into neuronal inclusions and exerts a gain of toxic function, which leads to neuronal toxicity and degeneration,3 similarly to what happens in Huntington’s disease and other SCAs.4

The longer the CAGexp at ATXN3, the earlier the age at onset (AO) of disease. A large body of evidence has established that AO is not entirely explained by CAGexp, which explains 50% to 60% of the variability in AO,5–8 and that AO should be modulated by additional genetic and/or environmental factors. Several candidates have been proposed, such as apolipoprotein E genotypic status,9–11 CAG length at normal ATXN3 8 12 13 and ATXN2 6 8 alleles, and protein levels of the DNAJB1 chaperone.14

Most of the proposed modifiers in SCA3/MJD were not replicated or had small effects that usually improve the explanation of AO variance by not more than 1%. The greater part of the missing variability in AO remains unexplained, suggesting that the main CAGexp-independent modulators of AO are still unknown. Here, we performed a systematic review and meta-analysis of genetic risk factors associated to AO in SCA3/MJD. By analysing both aggregate and individual-participant data of more than 2000 patients from 16 countries across three continents, we were able to detect an important origin-specific effect of CAGexp on AO and to confirm the effect of some putative risk factors published previously.

Methods

A detailed methodology protocol for this study was registered at the PROSPERO (International Prospective Register of Systematic Reviews) database prior to data extraction and is available at https://www.crd.york.ac.uk/PROSPERO/ under record CRD42017073071.

Literature search and data extraction

MEDLINE (PubMed), LILACS and EMBASE were searched from January 1994 to September 2017 for reports on genetic factors related to AO in SCA3/MJD. Search terms employed were ‘sca3’ OR ‘mjd’ OR ‘spinocerebellar ataxia type 3’ OR ‘spinocerebellar ataxia type-3’ OR ‘machado-joseph disease’ OR ‘machado joseph disease’ AND ‘age of onset’ OR ‘age-of-onset’ OR ‘age at onset’ OR ‘age-at-onset’. Peer-reviewed articles and meeting abstracts were included, and references were checked to guarantee maximal coverage. Two reviewers (EPDM and MKM) independently assessed and extracted data into evidence tables. Any disagreement regarding eligibility was discussed with a third reviewer (LBJ).

Population, exposure, comparators, outcomes, and inclusion and exclusion criteria

SCA3/MJD heterozygotes from diverse geographical origins comprised the population under study. The CAG length at CAGexp was the main exposure considered for meta-analysis; other genetic variants were included in the meta-analysis as risk factors (exposures) if reported at least twice in literature. The outcome was the quantitative variable AO defined as the age at the first symptom, usually gait ataxia. Included studies should report on both (1) molecularly confirmed SCA3/MJD symptomatic and/or asymptomatic heterozygotes and (2) the relationship between ATXN3 CAGexp (main exposure) and AO (outcome). The term ‘carrier’ was used here as a synonym for heterozygotes, symptomatic or not, with one ATXN3 allele with ≥45 CAG repeats. We excluded studies reporting on <20 carriers, in languages other than English, Portuguese or Spanish. If multiple publications reported the same data, the most up-to-date and complete data set was included. Corresponding authors were contacted to check for duplicated data and to grant access to their updated, pseudonymised, individual-participant databases (IPDs), whenever possible. Otherwise, we used summary statistics from aggregated databases (ADs). Besides AO and CAGexp, data on gender, family, length of normal ATXN3 CAG tracts and at other CAG-containing loci and/or additional genetic variants were retrieved, if available.

Risk of bias assessment and quality control

The outcome AO was poorly defined in some studies. Since most patients with SCA3/MJD develop gait ataxia as the first symptom,15 we combined in a single model carriers with known AO of gait ataxia (AOga) or of first symptom; when both criteria were available for the same individual, AOga was chosen. Only studies that measured CAG repeats by capillary electrophoresis were considered. Participation in molecular diagnosis quality control programmes was also questioned and informed here.

Analysis and data synthesis

Boxplots were used to describe the variability on both AO and CAGexp among studies. The meta-analysis was composed of three main models. First, the global relationship between ATXN3 CAGexp length and AO was investigated using data from both IPDs and ADs,16 aiming at comparing the degree of explanation of the variability in AO by CAGexp across studies, as reported by the linear R2 measure. A second meta-analysis used IPDs only. Since complex models (quadratic and logarithmic) were only marginally better at explaining the data (see online supplementary file 1), AO was not mathematically transformed, and linear regression was used. A third analysis tested the effects of gender, family and CAG length at the non-expanded ATXN3 allele and at other CAG-containing loci, focusing on the improvement of the R2 measure. Geographical origin and interaction between origin and CAGexp were always included as independent variables. With the exception of ATXN1, which was considered a continuous variable, the effect of all CAG-containing loci was assessed as both continuous and discrete variables using CAG length groups as published previously6 8 (online supplementary file 2). The percentage of AO variability explained by belonging to the same family was tested with a fixed-effects model. Analyses were performed using the software R V.3.4.1 with packages lsmeans and lmSupport, and SAS OnDemand for Academics V.3.1 (SAS Institute). Graphs were generated with ggplot2. Results were considered statistically significant when p<0.05.

Supplementary data

Supplementary data

Results

Systematic review

The search yielded 641 unique abstracts (online supplementary file 3); 140 studies testing the relationship between AO and CAGexp at ATXN3 were selected for the systematic review (online supplementary file 4). Thirty-one studies investigated additional modifying effects on AO, including CAG repeat length at the non-expanded ATXN3 (n=19), ATXN1 (n=5), ATXN2 (n=6), CACNA1A (n=7), ATXN7 (n=4), HTT (n=4), TBP (n=3) and ATN1 (n=4) alleles. AO differences according to length of GGGGCC repeats at C9ORF72, and CAG repeats at RAI1 and KCNN3 were each reported once. Another report correlated ataxin-3 and selected chaperones protein levels with AO. Allelic and/or genotypic status of single-nucleotide polymorphisms at 15 genes were also correlated with AO, including variants at ATXN3 (rs3814834, rs709930 and rs910369; n=1 each), APOE (rs429358 and rs7412; n=4) and ATXN2 (rs7969300), BDNF (rs6265), BECN1 (rs60221525 and rs116943570), CHIP (rs6597), hCAD (rs12738235), IL1A (rs1800587), IL1B (rs16944), IL6 (rs1800795), MT-ND3 (rs2853826), OGG1 (rs1052133), PPARGC1A (rs7665116), TNF (rs1800629) and UCHL1 (rs5030732; n=1 each). Differences in AO according to the degree of promoter methylation at ATXN3 were evaluated by two studies, using distinct methodologies. Gender of the affected individual and transmitting parent were correlated with AO in 14 and 6 studies, respectively. Two reports considered the effect of population of origin on AO, and one evaluated the familial dependency of AO. Data extraction, references and detailed information of all AO modifiers reported in the literature, including those not selected for meta-analysis, are described in online supplementary file 5.

Supplementary data

Supplementary data

Supplementary data

After contacting all corresponding authors of studies that met the inclusion and exclusion criteria (n=11), we retrieved updated information on 10 non-overlapping IPDs and 2 ADs of symptomatic individuals only (figure 1). CAGexp and geographical origin were available for all IPDs. Additional data included length of non-expanded CAG tracts at ATXN3 (n=9 cohorts), and at ATXN1, ATXN2, CACNA1A and ATXN7 (n=4 cohorts). Information on gender and family effects were available for six and seven cohorts, respectively. Geographical origin, sample sizes and retrieved data for each cohort included in the meta-analysis are summarised in table 1 and detailed in online supplementary file 6.

Supplementary data

Table 1

Studies selected for meta-analysis of the modulation of age at onset in SCA3/MJD by CAG repeat length at ATXN3 and additional factors

Figure 1

Workflow of the studies selected for the present meta-analysis.

Effect of CAGexp and geographical origin

Exposure to diverse CAGexp repeat lengths at ATXN3 was the most studied risk factor. IPD and AD retrieved from 11 studies comprised four cohorts from Europe,6 7 17 18 three from Asia,8 19 20 one from North America,6 one from Central America21 and three from Brazil.5 22 23 Brazilian cohorts comprised the Rio Grande do Sul (Brazil-RS) cohort23 and cohorts from other Brazilian regions (Brazil-non-RS cohorts): namely, subjects from São Paulo State22 and those described by Neurogenetics Network, a consortium of Brazilian researchers.5 Using both IPDs and ADs, the global linear correlation coefficient between CAGexp and log10(AO) was r=−0.743 (95% CI -0.768 to -0.713, p<0.001), meaning that, on average, the causative mutation determines about 55.2% (50.8%–59.0%) of the AO variability in SCA3/MJD worldwide.

Subsequent analyses used IPD cohorts only, totaling 2099 patients. Variability of CAGexp length among the 10 cohorts (figure 2A) was wider than variability in AO (figure 2B). Inclusion of geographical origin increased in 8.34% the explanation of AO variability (adjusted R2=0.556; F10,2091=263.8, p<0.001; online supplementary file 1). CAGexp significantly interacted with origin, which improved the model by an additional 1.02% (adjusted R2=0.564; F19,2082=144.1, p<0.001). The differential effect of CAGexp on AO among the 10 cohorts was evidenced by differences in slope and position of regression lines (figure 3A and B). Pairwise analysis of cohorts with similar slopes and/or intercepts allowed for data aggregation into three main geographical/ethnic groups with differential CAGexp modulation of AO: an average group with heterogeneous origins (China, Cuba, Brazil-non-RS and Taiwan cohorts), the group of non-Portuguese Europe (EUROSCA and Netherlands cohorts) and the group with clear Portuguese origin (Azorean Islands, mainland Portugal and Brazil-RS cohorts) (figure 3C and D; online supplementary file 7). Table 2 presents mean AO predictions for each geographically distinct group as a function of CAGexp tracts of three different lengths.

Supplementary data

Table 2

Effect of population of origin on the age at onset (AO) in SCA3/MJD

Figure 2

Variability of CAG length at the expanded ATXN3 allele and age at onset in SCA3/MJD. Data on CAG length at the expanded ATXN3 allele and age at onset are shown for the 10 original, individual-participant data cohorts selected for meta-analysis. EUROSCA, European Consortium on Spinocerebellar Ataxias; SCA3/MJD, spinocerebellar ataxia type 3/Machado-Joseph disease.

Figure 3

Population-specific modulation of the age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease. (A) Linear regression of CAGexp and AO in the 10 distinct cohorts included in the present meta-analysis (cohorts are colour-coded as in panel B). (B) Same as in (A), but with individual plots for each cohort. The β coefficient of the linear regression, expressed as mean±SE, is also shown for each cohort. (C) Same as in (A), but with patients grouped in three main geographical origins, as a result of pairwise comparisons of intercepts and slopes of lines presented in (A). (D) Same as in (C), but with geographical origins depicted separately. Hexagons depict groups of patients, according to the colour scheme, and dashed lines represent linear regressions. For each plot, the R2 correlation coefficient is also shown. EUROSCA, European Consortium on Spinocerebellar Ataxias.

Effect of non-expanded CAG repeats at ATXN3 and other CAG-containing loci

Data on CAG length of non-expanded ATXN3, ATXN1, ATXN2, CACNA1A and ATXN7 alleles were available from 944 patients from four cohorts (EUROSCA, Azorean Islands, Brazil-RS and Brazil-non-RS) for meta-analysis. Inclusion of CAG length at the non-expanded ATXN3 allele did not significantly improve the correlation between CAGexp and AO (p=0.327, continuous variable; p=0.388, discrete variable; online supplementary file 1). From the remaining candidate loci, only ATXN2 significantly improved the explanation of AO variability, with longer ATXN2 CAG tracts correlating with earlier AO (adjusted R2=0.630; F10,933=161.6, p<0.001; online supplementary file 1). There was a significant interaction between length of the longest CAG tract at ATXN2 and CAGexp, which contributed an additional 0.39% to the explanation of AO variability (p=0.020; online supplementary file 1). Presence of at least one intermediate ATXN2 allele (27–33 CAGs; 5% of alleles) significantly correlated with earlier AO (adjusted R2=0.632; F13,930=125.7, p<0.001; figure 4A and online supplementary file 1) in individuals with CAGexp tracts of up to 73 repeats (table 3).

Figure 4

Effect of co-modifiers of the age at onset (AO) in SCA3/MJD. (A) Linear regression of CAG repeat length at the expanded ATXN3 allele (CAGexp) and AO in patients with spinocerebellar ataxia type 3/Machado-Joseph disease, divided into four categories according to length of CAG tracts at both ATXN2 alleles. I, at least one short (<22) allele; II, homozygous medium (22) alleles; III, at least one short intermediate allele (23–26) with or without a medium (=22) allele; IV, at least one intermediate (27–33) allele. (B) Same as in (A) but with individuals divided according to gender.

Table 3

Effect of ATXN2 genotypes on the age at onset (AO) in SCA3/MJD

Family and gender effects

Information on family effects was available for 1368 patients from 565 families (online supplementary file 8). Among these, CAGexp and origin alone explained ~60% of AO variance (adjusted R2=0.599; F11,1356=186.8; p<0.001). Inclusion of family data in a fixed-effects model increased the explanation by ~10% (adjusted R2=0.702; F888,479=4.6; p<0.001; online supplementary file 1). Data on gender were available for 1468 patients, and its inclusion contributed an additional 0.3% increase in the explanation of variability in AO (adjusted R2=0.590; F10,1457=211.9; p<0.001; online supplementary file 1). On average, male patients had younger ages at onset, especially among individuals with longer CAGexp tracts (figure 4B and online supplementary file 9). However, when considered together with CAG repeat length at ATXN2 (n=942 individuals), the effect of gender was not significant (p=0.08; online supplementary file 1).

Supplementary data

Supplementary data

Combined effects

The final and best regression model considered CAGexp, origin, family effects and ATXN2 genotypes, and explained 73.5% (95% CI 68.2 to 77.6) of the AO variance (adjusted R2=0.735; F682,245=4.8; p<0.001; online supplementary file 1).

Discussion

This worldwide systematic investigation of risk factors for AO in SCA3/MJD detected that the CAGexp determines, on average, 55.2% of the phenotypic variability in AO. Additional modulation of AO by family factors, gender and CAG length at ATXN2 were confirmed. Interestingly, currently unknown effectors related to geographical origin were also shown to modify AO. Although several more candidates have already been proposed, data were not robust enough to be meta-analysed, and further replication studies are necessary to assess their validity as phenotypic modulators in SCA3/MJD.

Effect of CAGexp and geographical/ethnic and family background

Clear geographical/ethnic differences on the effect of CAGexp on AO tell us that a universal correlation might not applicable to all carrier populations. Choice of statistical modelling might further evidence how populational differences in CAGexp can impact AO determination. Significant increase in explanation of AO variability was detected in Han Chinese,8 European carriers from non-Portuguese populations and Americans6 using quadratic models. Here, the quadratic modelling of CAGexp from IPDs yielded only a marginal improvement when compared with a simpler, linear regression modelling of AO variance. This is likely attributed to presence of individuals with larger CAGexp tracts (figure 2A), which correlate more strongly with AO,7 compared with previous publications.6 8

Variation of CAGexp distribution was markedly larger than variation of AO among populations (figure 2). SCA3/MJD populations with larger CAGexp belonged to Brazilian and Asian cohorts. Inversely, subjects from Austria, Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain and UK (EUROSCA cohort)6 had the shortest mean CAGexp. Reasons for such differences are still unknown. Although ascertainment bias usually operates in favour of recruiting more severe cases (ie, longer CAGexp tracts), this bias was unlikely in at least one cohort (Brazil-RS) with large CAGexp tracts since coverage in this population was shown to be very high.23 Substantial differences in CAGexp determination are also unlikely since most included studies were performed in laboratories engaged in molecular diagnosis quality control programmes. Therefore, distinct CAGexp patterns likely represent true differences related to population of origin.

Pairwise comparisons allowed us to categorise carriers into three main geographical/ethnic groups, reflecting distinct relationships between CAGexp and AO (figure 3 and table 2), and suggesting that CAGexp does not have the same effect on AO of all SCA3/MJD carriers worldwide. Assuming that the ‘average’ group (figure 3C,D) represents the worldwide average relationship between CAGexp and AO in SCA3/MJD, our analysis suggests the existence of AO modifiers with opposing effects on non-Portuguese European carriers versus subjects with Portuguese ancestry (mainland Portuguese, Azorean and South Brazilians). There seems to be factors among non-Portuguese Europeans and carriers of Portuguese ancestry that effectively predispose to earlier and later AO, respectively, given a CAGexp of same length. It is also possible that the geographical/ethnic effect uncovered here reflects, at least partially, distinct ATXN3 haplotypes and mutational origins, as different SCA3/MJD populations show distinct haplotypic frequencies.24 Further research will be necessary to establish a causal link, if any, between CAGexp haplotypes and AO.

Familial effects might also be due to genetic AO modifiers, although the effect of shared environmental exposures within a family cannot be excluded. A significant decrease in residual AO variance within families, compared with that between families, was observed previously.18 25 The ~10% improvement in R2 observed here was smaller than the 25% observed in a French and Dutch cohort18; whether this was due to presence of several small families with one or two individuals in the meta-analysis remains to be established (online supplementary file 8).

Effect of the non-expanded ATXN3 allele and of other non-expanded CAG-containing loci

In agreement with most original studies, there was no association between length of the non-expanded ATXN3 allele and AO (online supplementary files 1 and 5) and that was also the case for ATXN1, ATXN7 and CACNA1A. However, since we did not have access to IPD from the large Chinese cohort that reported the associations between AO and CACNA1A and ATXN7,8 population-specific differences in the range of CAG tracts at these loci—and in power to detect their potential effects—should not be overruled.

In contrast, we confirmed the association between non-expanded ATXN2 alleles of intermediate CAG length (27–33 repeats) and earlier AO in SCA3/MJD (figure 4A, table 3 and online supplementary file 1), as reported previously.6 8 Lack of confirmation in other cohorts is most likely attributed to small sample sizes6 7 or inclusion of ATXN2 in regression analysis as a continuous variable.5 Whether the modulatory effect of ATXN2 would be due to the CAG tract directly, or another genetically linked variant, is still unknown. Several observations support a biologically significant role for ATXN2 and the normal ataxin-2 protein in neurodegenerative diseases. For instance, longer non-expanded ATXN2 alleles have been related to increased risk of developing amyotrophic lateral sclerosis,26 progressive supranuclear palsy,27 frontotemporal dementia28 and multiple systems atrophy.29 Outside the CAG tract, a correlation between a missense polymorphism at ATXN2 and earlier AO in Chinese patients with SCA3/MJD was recently shown.30 Moreover, lower ataxin-2 levels were detected in brains of patients with SCA3/MJD and transgenic mice compared with healthy controls.31 Importantly, restoration of ataxin-2 levels in affected mice led to significant morphological and behavioural improvements.31 Therefore, the current evidence suggests that ataxin-2 is a strong candidate modifier of AO (and, maybe, disease progression) in SCA3/MJD.

Study limitations

Although great care was taken to control for potential biases and confounding factors, the present study is not without methodological limitations. Importantly, due to its retrospective assessment, it is possible that AO was not precisely defined for some of the individuals included. However, recalling biases were likely present in all patient cohorts, thus arguing in favour of true differences in AO among carriers from distinct populations/ethnicities. Moreover, different studies selected for meta-analysis had distinct definitions of AO, namely AO of the first symptom or AO of gait ataxia. Even though gait ataxia is usually the first symptomatic manifestation of SCA3/MJD, other symptoms might present before gait abnormalities.15 While some of the largest patient cohorts included in this study had gait ataxia clearly stated as the parameter of choice for AO, which might have contributed to reduce AO heterogeneity, it is possible that distinct AO parameters are differentially modulated by CAGexp and/or other genetic factors.

Concluding remarks

The present analysis estimated that CAGexp is globally responsible for 55.2% of AO variance, on average. Gender and shared familial characteristics (most likely genetic) were confirmed as factors that influence AO in SCA3/MJD. Among candidate genes, CAG length at ATXN2 was the only variant confirmed by the meta-analysis; future studies on the ataxin-3/ataxin-2 interactions might disclose promising discoveries.

Moreover, the IPD meta-analysis suggested protective factors in SCA3/MJD geographical groups of Portuguese origin, and probably a lack of some protective factors in non-Portuguese Europeans. Studying selected SCA3/MJD carrier groups, such as cohorts from specific geographical origins, or families with disease onset markedly different from the expected AO for their location, could significantly boost the search for genetic AO modulators.

The best model to assess the effect of the confirmed independent variables on AO determination in SCA3/MJD included CAGexp, geographical origin, family and CAG length at ATXN2: this model explained 73.5% of AO variability. That does not mean that factors responsible for the remaining variance should not have a genetic nature as well. In fact, several studies reviewed here assessed the effect of other genetic variants on AO, and some had promising results. Unfortunately, most were unique studies that were not qualified for meta-analysis. However, one of the advantages of meta-analyses is that updates can be performed in the future. Hopefully, further evidences on modifiers could increase the explanation of AO variability in SCA3/MJD, disclosing factors with potential therapeutic roles.

Acknowledgments

This work would not be possible without the collaborative efforts of many people. We would like to thank all patients and corresponding authors of selected studies for sharing their data with us. This work was supported by the following Brazilian agencies: CAPES—Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Project 99999.01528/2015-2017; CNPq—Conselho Nacional de Desenvolvimento Científico e Tecnológico, Project 402968/2012-3; FIPE-HCPA—Fundo de Incentivo à Pesquisa do Hospital de Clínicasde Porto Alegre, Projects GPPG HCPA 13-0303 and 14-0204. EPDM, MLS-P and LBJ were supported by CNPq.

References

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Footnotes

  • Correction notice Since this paper was first published online, the author name Vanessa Leotti Torman has been updated to Vanessa Bielefeldt Leotti.

  • Contributors EPDM, MLS-P and LBJ designed the study. EPDM, MKM and LBJ performed the systematic review. EPDM and VBL performed the statistical analysis. EPDM, MKM, VBL, MLS-P and LBJ wrote the manuscript.

  • Funding This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant no. 402968/2012-3), Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (grant no. GPPG HCPA 13-0303GPPG HCPA 14-0204) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (grant no. 99999.01528/2015-2017).

  • Disclaimer Funding organisations had no role in study design; collection, analysis and interpretation of data; writing of the report; or decision to submit the article for publication.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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