Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing.
medRxiv
; 2023 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-38076956
ABSTRACT
Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. We previously mapped the genetic regulation of gene expression and mRNA splicing in human microglia, identifying several loci where common genetic variants in microglia-specific regulatory elements explain disease risk loci identified by GWAS. However, identifying genetic effects on splicing has been challenging due to the use of short sequencing reads to identify causal isoforms. Here we present the isoform-centric microglia genomic atlas (isoMiGA) which leverages the power of long-read RNA-seq to identify 35,879 novel microglia isoforms. We show that the novel microglia isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ethnic meta-analysis of 555 human microglia short-read RNA-seq samples from 391 donors, the largest to date, and found associations with genetic risk loci in Alzheimer's disease and Parkinson's disease. We nominate several loci that may act through complex changes in isoform and splice site usage.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
MedRxiv
Year:
2023
Document type:
Article
Affiliation country:
Estados Unidos