Genetic architecture of RNA editing regulation in Alzheimer’s disease across diverse ancestral populations
Year: 2022
Type: article
Study design: Observational Study
Abstract: Most Alzheimer's disease (AD)-associated genetic variants do not change protein coding sequence and thus likely exert their effects through regulatory mechanisms. RNA editing, the post-transcriptional modification of RNA bases, is a regulatory feature that is altered in AD patients that differs across ancestral backgrounds. Editing QTLs (edQTLs) are DNA variants that influence the level of RNA editing at a specific site. To study the relationship of DNA variants genome-wide, and particularly in AD-associated loci, with RNA editing, we performed edQTL analyses in self-reported individuals of African American (AF) or White (EU) race with corresponding global genetic ancestry averaging 82.2% African ancestry (AF) and 96.8% European global ancestry (EU) in the two groups, respectively. We used whole-genome genotyping array and RNA sequencing data from peripheral blood of 216 AD cases and 212 age-matched, cognitively intact controls. We identified 2144 edQTLs in AF and 3579 in EU, of which 1236 were found in both groups. Among these, edQTLs in linkage disequilibrium (r2 > 0.5) with AD-associated genetic variants in the SORL1, SPI1 and HLA-DRB1 loci were associated with sites that were differentially edited between AD cases and controls. While there is some shared RNA editing regulatory architecture, most edQTLs had distinct effects on the rate of RNA editing in different ancestral populations suggesting a complex architecture of RNA editing regulation. Altered RNA editing may be one possible mechanism for the functional effect of AD-associated variants and may contribute to observed differences in the genetic etiology of AD between ancestries.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddac075
Authors: Olivia K Gardner, Derek Van Booven, Lily Wang, Tianjie Gu, Natalia K Hofmann, Patrice L Whitehead, Karen Nuytemans, Kara L Hamilton-Nelson, Larry D Adams, Takiyah D Starks, Michael L Cuccaro, Eden R Martin, Jeffery M Vance, William S Bush, Goldie S Byrd, Jonathan L Haines, Gary W Beecham, Margaret A Pericak-Vance, Anthony J Griswold
Language: English
Topic: RNA regulation and disease
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Genomic, Epigenomic, and Transcriptomic Mechanisms of Contributing to Alzheimer's Disease Risk in Diverse Ancestral Populations, Genetic Epidemiology of Alzheimer's Disease in African Americans, Wake Forest Clinical and Translational Science Award, G2074902036, G3083277455, G3089426657, Genomic Convergence in Alzheimer Disease, G4037773979, Replication and Extension of ADSP Discoveries in African-Americans, Alzheimer's Disease Genetics Consortium, G5437871763, The Origins of Alzheimer Disease in Individuals of African Ancestry, Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry, The Origins of Alzheimer Disease in African Americans, Genomic, Epigenomic, and Transcriptomic Mechanisms of Contributing to Alzheimer's Disease Risk in Diverse Ancestral Populations, G919295597
OpenAlex ID: W4226026001