Matches in SemOpenAlex for { <https://semopenalex.org/work/W2950200189> ?p ?o ?g. }
- W2950200189 abstract "ABSTRACT Neurodegenerative diseases pose an extraordinary threat to the world’s aging population, yet no disease-modifying therapies are available. While genome-wide association studies (GWAS) have identified hundreds of novel risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Indeed, of the many thousands of SNP-trait associations identified by GWAS over the past ~10 years, very few are understood mechanistically. Here, we investigate the association of common genetic variants at the 7p21 locus with risk for the neurodegenerative disease frontotemporal lobar degeneration. We show that variants associated with disease risk correlate with increased brain expression of the 7p21 gene TMEM106B , and no other genes. Furthermore, incremental increases in TMEM106B levels result in incremental increases in lysosomal phenotypes and cell toxicity. We then combine fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, which differentially recruits CTCF, influencing CTCF-mediated long-range chromatin looping interactions between multiple cis -regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWAS to frontotemporal lobar degeneration, nominating a causal variant and a causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk for neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in brain CTCF-binding sites genome-wide, implicating CTCF-mediated gene regulation in risk for neurodegeneration more generally." @default.
- W2950200189 created "2019-06-27" @default.
- W2950200189 creator A5005477723 @default.
- W2950200189 creator A5008969134 @default.
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- W2950200189 creator A5048392622 @default.
- W2950200189 creator A5049867340 @default.
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- W2950200189 creator A5055631788 @default.
- W2950200189 creator A5060338666 @default.
- W2950200189 creator A5069461209 @default.
- W2950200189 creator A5084454080 @default.
- W2950200189 creator A5089470275 @default.
- W2950200189 date "2017-06-24" @default.
- W2950200189 modified "2023-10-07" @default.
- W2950200189 title "A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression" @default.
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- W2950200189 doi "https://doi.org/10.1101/154989" @default.