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Interpreting Gene Expression Effects of Disease-Associated Variants: A Lesson from SNCA rs356168.

ABSTRACT: The SNCA intronic single nucleotide polymorphism (SNP), rs356168, has been associated with Parkinson's disease (PD) in large genome wide association studies (GWAS). Recently, the PD-risk allele, rs356168-G was shown to increase SNCA-mRNA expression using genome edited human induced pluripotent stem cells (iPSC)-derived neurons. In this study, as means of validation, we tested the effect of rs356168 on total SNCA-mRNA levels using brain tissues, temporal and frontal cortex, from healthy control donors. Carriers of the rs356168-G allele demonstrated a borderline significant decrease of SNCA-mRNA levels in temporal brain tissues (p = 0.02) compared to individuals homozygous for the 'A' allele. Similar trend, but weak, was observed in the analysis of frontal cortex samples, however, this analysis did not reach statistical significance. These results conflict with the recently reported effect of SNCA SNP rs356168 described above. Our study conveys the need to carefully interpret the precise molecular mechanism by which rs356168, or another tightly linked variant, affects the regulation of SNCA expression. The regulatory mechanisms that contribute to the observed associations between PD and the SNCA-3' linkage disequilibrium region warrant further investigations.

SUBMITTER: Glenn OC

PROVIDER: S-EPMC5611418 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Interpreting Gene Expression Effects of Disease-Associated Variants: A Lesson from SNCA rs356168.

Glenn Omolara-Chinue OC Tagliafierro Lidia L Beach Thomas G TG Woltjer Randy L RL Chiba-Falek Ornit O

Frontiers in genetics 20170920

The SNCA intronic single nucleotide polymorphism (SNP), rs356168, has been associated with Parkinson's disease (PD) in large genome wide association studies (GWAS). Recently, the PD-risk allele, rs356168-G was shown to increase SNCA-mRNA expression using genome edited human induced pluripotent stem cells (iPSC)-derived neurons. In this study, as means of validation, we tested the effect of rs356168 on total SNCA-mRNA levels using brain tissues, temporal and frontal cortex, f ...[more]

PMID: 28979294

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Project description:Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in synucleinopathies representing an attractive strategy to elucidate-common and specific-SNCA-genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.

Dataset Information

Interpreting Gene Expression Effects of Disease-Associated Variants: A Lesson from SNCA rs356168.

Publications

Interpreting Gene Expression Effects of Disease-Associated Variants: A Lesson from <i>SNCA</i> rs356168.

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