Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing

Journal article

Jack Humphrey, Erica Brophy, R. Kosoy, Biao Zeng, Elena Coccia, Daniele Mattei, Ashvin Ravi, Anastasia G. Efthymiou, Elisa Navarro, Benjamin Z Muller, G. J. Snijders, Amanda Allan, Alexandra Münch, Reta Birhanu Kitata, S. Kleopoulos, S. Argyriou, Z. Shao, Nancy Francoeur, Chia-Feng Tsai, Marina A. Gritsenko, M. Monroe, V. Paurus, K. Weitz, Tujin Shi, R. Sebra, Tao Liu, L. D. de Witte, A. Goate, D. Bennett, V. Haroutunian, G. Hoffman, J. Fullard, P. Roussos, Towfique Raj
medRxiv, 2023

Semantic Scholar DOI PubMedCentral PubMed

Cite

APA Click to copy
Humphrey, J., Brophy, E., Kosoy, R., Zeng, B., Coccia, E., Mattei, D., … Raj, T. (2023). Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing. MedRxiv.

Chicago/Turabian Click to copy
Humphrey, Jack, Erica Brophy, R. Kosoy, Biao Zeng, Elena Coccia, Daniele Mattei, Ashvin Ravi, et al. “Long-Read RNA-Seq Atlas of Novel Microglia Isoforms Elucidates Disease-Associated Genetic Regulation of Splicing.” medRxiv (2023).

MLA Click to copy
Humphrey, Jack, et al. “Long-Read RNA-Seq Atlas of Novel Microglia Isoforms Elucidates Disease-Associated Genetic Regulation of Splicing.” MedRxiv, 2023.

BibTeX Click to copy

@article{jack2023a,
  title = {Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing},
  year = {2023},
  journal = {medRxiv},
  author = {Humphrey, Jack and Brophy, Erica and Kosoy, R. and Zeng, Biao and Coccia, Elena and Mattei, Daniele and Ravi, Ashvin and Efthymiou, Anastasia G. and Navarro, Elisa and Muller, Benjamin Z and Snijders, G. J. and Allan, Amanda and Münch, Alexandra and Kitata, Reta Birhanu and Kleopoulos, S. and Argyriou, S. and Shao, Z. and Francoeur, Nancy and Tsai, Chia-Feng and Gritsenko, Marina A. and Monroe, M. and Paurus, V. and Weitz, K. and Shi, Tujin and Sebra, R. and Liu, Tao and de Witte, L. D. and Goate, A. and Bennett, D. and Haroutunian, V. and Hoffman, G. and Fullard, J. and Roussos, P. and Raj, Towfique}
}

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.