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No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a disorder with highly variable clinical phenotype. The identification of genetic variants modifying age at onset and other traits is of great interest because it may provide insight into disease mechanisms and potential therapeutic targets. A variant in the DNM3 gene (rs2421947) has been reported as a genetic modifier of age at onset in LRRK2-associated PD. To test the possible effect of genetic variation in DNM3 on age at onset in idiopathic PD, we examined rs2421947 in a total of 5918 patients with PD from seven data sets. We also assessed the potential effect of all common variants in the DNM3 locus. There was no significant association between rs2421947 and age at onset in any of the individual studies. Meta-analysis of the seven studies was nonsignificant and the between-study heterogeneity was minimal. No other common variants within the DNM3 locus affected age at onset. In conclusion, we find no evidence of an association between DNM3 variants and age at onset in idiopathic PD.

SUBMITTER: Berge-Seidl V

PROVIDER: S-EPMC6345552 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease.

Berge-Seidl Victoria V Pihlstrøm Lasse L Wszolek Zbigniew K ZK Ross Owen A OA Toft Mathias M

Neurobiology of aging 20180922

Parkinson's disease (PD) is a disorder with highly variable clinical phenotype. The identification of genetic variants modifying age at onset and other traits is of great interest because it may provide insight into disease mechanisms and potential therapeutic targets. A variant in the DNM3 gene (rs2421947) has been reported as a genetic modifier of age at onset in LRRK2-associated PD. To test the possible effect of genetic variation in DNM3 on age at onset in idiopathic PD, we examined rs242194 ...[more]

PMID: 30340792

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Project description:Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27-74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.

Dataset Information

No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease.

Publications

No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease.

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