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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月3日

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

摘要

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.