1. Frontotemporal degeneration genetic risk loci and transcription regulation as a possible mechanistic link to disease risk.
- Author
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Sawyer RP, Stone HK, Salim H, Lu X, Weirauch MT, and Kottyan L
- Subjects
- Atrophy, DNA, Gene Expression Regulation, Humans, Linkage Disequilibrium, Transcription Factors genetics, Transcription Factors metabolism, Frontotemporal Dementia genetics, Genome-Wide Association Study
- Abstract
The etiology of Frontotemporal Degeneration (FTD) is not well understood. Genetic studies have established common genetic variants (GVs) that are associated with increased FTD risk. We review previous genome wide association studies (GWAS) of FTD and nominate specific transcriptional regulators as potential key players in the etiology of this disease. A list of GVs associated with FTD was compiled from published GWAS. The regulatory element locus intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk GVs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation (ChIP-seq) experiments. After linkage disequilibrium expansion of the previously reported tag associated GVs, we identified 914 GV at 47 independent risk loci. Using the RELI algorithm, we identified several transcriptional regulators with enriched binding at FTD risk loci (0.05 < corrected P value <1.18 × 10-27), including Tripartite motif-containing 28 (TRIM28) and Chromodomain-Helicase DNA-binding 1 (CHD1) which have previously observed roles in FTD. FTD is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established FTD risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response as important in the genetic etiology of FTD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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