Dataset Information

Investigating FUS variation in Parkinson's disease.

ABSTRACT: Mutations of the FUS gene were first reported to cause amyotrophic lateral sclerosis (ALS). Subsequent studies confirmed the role of mutations in ALS and also implicated them in frontotemporal dementia (FTD). Recently, through Next-Generation Exome sequencing approaches a mutation resulting in a substitution (p.Q290X) in the nuclear export domain of the FUS protein was nominated as a cause of autosomal dominant essential tremor (ET) in a large kindred. In addition, recent reports suggest a possible role for TDP-43 mutations in parkinsonism; TDP-43 is another RNA-binding protein implicated in ALS. Given these findings we investigated the role of FUS variants in Parkinson's disease (PD). We sequenced specific regions of the gene encoding three functional domains of the FUS protein in 702 patients with PD. Our sequencing study did not identify any novel non-synonymous variant that would appear to affect the subjects' susceptibility to Parkinson's disease. These findings and previous studies have shown that variants within the FUS gene are not a common cause of PD or ET, in comparison to their role in ALS.

SUBMITTER: Labbe C

PROVIDER: S-EPMC4721223 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Investigating FUS variation in Parkinson's disease.

Labbé Catherine C Rayaprolu Sruti S Soto-Ortolaza Alexandra A Ogaki Kotaro K Uitti Ryan J RJ Wszolek Zbigniew K ZK Ross Owen A OA

Parkinsonism & related disorders 20140101

Mutations of the FUS gene were first reported to cause amyotrophic lateral sclerosis (ALS). Subsequent studies confirmed the role of mutations in ALS and also implicated them in frontotemporal dementia (FTD). Recently, through Next-Generation Exome sequencing approaches a mutation resulting in a substitution (p.Q290X) in the nuclear export domain of the FUS protein was nominated as a cause of autosomal dominant essential tremor (ET) in a large kindred. In addition, recent reports suggest a possi ...[more]

PMID: 24262168

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Project description:There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson's disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson's disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson's disease (28 568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = -2.364, 95% confidence interval (CI) = -4.789-0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease.

Project description:BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Dataset Information

Investigating FUS variation in Parkinson's disease.

Publications

Investigating FUS variation in Parkinson's disease.

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