Dataset Information

The Association between C9orf72 Repeats and Risk of Alzheimer's Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis.

ABSTRACT: C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. However, the relationship between C9orf72 repeats and Alzheimer's disease (AD) was not clear. Additionally, there were few articles assessing C9orf72 in other ethnicities with ALS. In this meta-analysis, we aimed to investigate the relationship between C9orf72 repeat expansions (?30 repeats) and intermediate repeat copies (20-29 repeats) and AD or ALS. The results suggested positive correlations between C9orf72 repeat expansions and the risk of Alzheimer's disease (OR = 6.36, 95% CI = 3.13-12.92, and p < 0.00001), while intermediate repeat copies of C9orf72 gene were not associated with the risk of the disease. C9orf72 repeat expansions were positively correlated with the risk of familial and sporadic ALS (OR = 293.25, 95% CI = 148.17-580.38, and p < 0.00001; OR = 35.57, 95% CI = 19.61-64.51, and p < 0.00001). There was a positive correlation between the gene variations and ALS risk among Caucasians and Asians (OR = 57.56, 95% CI = 36.73-90.22, and p < 0.00001; OR = 6.35, 95% CI = 1.39-29.02, and p = 0.02).

SUBMITTER: Shu L

PROVIDER: S-EPMC4916312 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Association between C9orf72 Repeats and Risk of Alzheimer's Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis.

Shu Li L Sun Qiying Q Zhang Yuan Y Xu Qian Q Guo Jifeng J Yan Xinxiang X Tang Beisha B

Parkinson's disease 20160608

C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. However, the relationship between C9orf72 repeats and Alzheimer's disease (AD) was not clear. Additionally, there were few articles assessing C9orf72 in other ethnicities with ALS. In this meta-analysis, we aimed to investigate the relationship between C9orf72 repeat expansions (≥30 repeats) and intermediate repeat copies (20-29 repeats) and AD or ALS. The r ...[more]

PMID: 27375918

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Project description:An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed.Gene expression profiling utilised total RNA extracted from motor neurons and lymphoblastoid cell lines derived from human ALS patients, including those with an expansion of C9ORF72, and controls. In lymphoblastoid cell lines, expansion length and the frequency of sense and antisense RNA foci was also examined.Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding 'RNA splicing' proteins. There was a significant overlap of these genes with an independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length.Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity.

Dataset Information

The Association between C9orf72 Repeats and Risk of Alzheimer's Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis.

Publications

The Association between C9orf72 Repeats and Risk of Alzheimer's Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis.

Similar Datasets

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