Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.

Nature genetics 2025

Humphrey Jack; Brophy Erica; Kosoy Roman; Zeng Biao; Coccia Elena; Mattei Daniele; Ravi Ashvin; Naito Tatsuhiko; Efthymiou Anastasia G; Navarro Elisa; De Sanctis Claudia; Flores-Almazan Victoria; Muller Benjamin Z; Snijders Gijsje J L J; Allan Amanda; Münch Alexandra; Kitata Reta Birhanu; Kleopoulos Steven P; Argyriou Stathis; Malakates Periklis; Psychogyiou Konstantina; Shao Zhiping; Francoeur Nancy; Tsai Chia-Feng; Gritsenko Marina A; Monroe Matthew E; Paurus Vanessa L; Weitz Karl K; Shi Tujin; Sebra Robert; Liu Tao; de Witte Lot D; Goate Alison M; Bennett David A; Haroutunian Vahram; Hoffman Gabriel E; Fullard John F; Roussos Panos; Raj Towfique

Abstract

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads. Here, we present the isoform-centric microglia genomic atlas (isoMiGA), which leverages long-read RNA sequencing to identify 35,879 novel microglia isoforms. We show that these isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ancestry meta-analysis of 555 human microglia short-read RNA sequencing samples from 391 donors, and found associations with genetic risk loci in Alzheimer’s and Parkinson’s disease. We nominate several loci that may act through complex changes in isoform and splice-site usage.

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