Dataset Information

Next-generation profiling to identify the molecular etiology of Parkinson dementia.

ABSTRACT:

Objective

We sought to determine the underlying cortical gene expression changes associated with Parkinson dementia using a next-generation RNA sequencing approach.

Methods

In this study, we used RNA sequencing to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex from neurologically normal control patients, patients with Parkinson disease, and patients with Parkinson disease with dementia.

Results

Genes overexpressed in both disease states were involved with an immune response, whereas shared underexpressed genes functioned in signal transduction or as components of the cytoskeleton. Alternative splicing analysis produced a pattern of immune and RNA-processing disturbances.

Conclusions

Genes with the greatest degree of differential expression did not overlap with genes exhibiting significant alternative splicing activity. Such variation indicates the importance of broadening expression studies to include exon-level changes because there can be significant differential splicing activity with potential structural consequences, a subtlety that is not detected when examining differential gene expression alone, or is underrepresented with probe-limited array technology.

SUBMITTER: Henderson-Smith A

PROVIDER: S-EPMC4881621 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Next-generation profiling to identify the molecular etiology of Parkinson dementia.

Henderson-Smith Adrienne A Corneveaux Jason J JJ De Both Matthew M Cuyugan Lori L Liang Winnie S WS Huentelman Matthew M Adler Charles C Driver-Dunckley Erika E Beach Thomas G TG Dunckley Travis L TL

Neurology. Genetics 20160524 3

<h4>Objective</h4>We sought to determine the underlying cortical gene expression changes associated with Parkinson dementia using a next-generation RNA sequencing approach.<h4>Methods</h4>In this study, we used RNA sequencing to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex from neurologically normal control patients, patients with Parkinson disease, and patients with Parkinson disease with dementia.<h4>Results</h4>Genes overexpressed in both di ...[more]

PMID: 27275011

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Project description:BackgroundAccumulating evidence implicates mitochondrial DNA (mtDNA) alleles, which are independent of the nuclear genome, in disease, especially in human metabolic diseases. However, this area of investigation has lagged behind in researching the nuclear alleles in complex traits, for example, in gout.MethodsNext-generation sequencing was utilized to investigate the relationship between mtDNA alleles and phenotypic variations in 52 male patients with gout and 104 age-matched male non-gout controls from the Taiwan Biobank whole-genome sequencing samples. Differences from a reference sequence (GRCh38) were identified. The sequence kernel association test (SKAT) was applied to identify gout-associated alleles in mitochondrial genes. The tools Polymorphism Phenotyping, Sorting Intolerant From Tolerant (SIFT), Predict the pathology of Mutations (PMUT), Human Mitochondrial Genome Database (mtDB), Multiple Alignment using Fast Fourier Transform (MAFFT), and Mammalian Mitochondrial tRNA Genes (Mamit-tRNA) were used to evaluate pathogenicity of alleles. Validation of selected alleles by quantitative polymerase chain reaction of single nucleotide polymorphisms (qPCR SNPs) was also performed.ResultsWe identified 456 alleles in patients with gout and 640 alleles in non-gout controls with 274 alleles shared by both. Mitochondrial genes were associated with gout, with MT-CO3, MT-TA, MT-TC, and MT-TT containing potentially pathogenic gout-associated alleles and displaying evidence of gene-gene interactions. All heteroplasmy levels of potentially pathogenic alleles exceeded metabolic thresholds for pathogenicity. Validation assays confirmed the next-generation sequencing results of selected alleles. Among them, potentially pathogenic MT-CO3 alleles correlated with high-density lipoprotein (HDL) levels (P?=?0.034).ConclusionThis study provided two scientific insights. First, this was the most extensive mitochondrial genomic profiling associated with gout. Second, our results supported the roles of mitochondria in gout and HDL, and this comprehensive analysis framework can be applied to other diseases in which mitochondrial dysfunction has been implicated.

Dataset Information

Next-generation profiling to identify the molecular etiology of Parkinson dementia.

Objective

Methods

Results

Conclusions

Publications

Next-generation profiling to identify the molecular etiology of Parkinson dementia.

Similar Datasets

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