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

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY Nature genetics Pub Date : 2025-03-03 DOI:10.1038/s41588-025-02099-0

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

{"title":"Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing","authors":"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","doi":"10.1038/s41588-025-02099-0","DOIUrl":null,"url":null,"abstract":"<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>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"29 1","pages":""},"PeriodicalIF":31.7000,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41588-025-02099-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

求助全文

约1分钟内获得全文去求助

来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution