ArticleNature genetics2025
Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.
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Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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26citing papers in PubMed, 1 pooled it
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26 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A meta-analysis of single-nucleus expression quantitative trait loci linking genetic risk to brain disorders.Nature genetics · 2026Pooled it
- Single-cell profiling and genetic regulation of alternative polyadenylation in the human brain.Nature genetics · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.Nature communications · 2026Article
- Long-Read RNA Sequencing Reveals an Isoform Switching Pattern in Healthy Microglial Cell Lines Exposed to Radiotherapy.Non-coding RNA · 2026Article
- Beyond the gene: isoform diversity as a key contributor to human brain disorders.Current opinion in genetics & development · 2026Review
- Gene- and Isoform-Level Responses to Extreme Acidic pH Stress in an Emerging Marine Invertebrate Model OrganismAntioxidants (Basel, Switzerland) · 2026Article
- An empirical Bayes framework for burden and dispersion association tests helps prioritize rare variants associated with Alzheimer's disease.medRxiv : the preprint server for health sciences · 2026Article
- Disease-associated genetic variants can cause missense effects in tissue-specific protein isoforms.Nature communications · 2026Article
- Native long-read RNA sequencing of human monocytes reveals activation-induced alternative splicing toward functional isoforms.Nature communications · 2026Article
- Long-read transcriptomics of purified human cortical cell types exposes glial isoform complexity and disease-relevant transcript architecture.bioRxiv : the preprint server for biology · 2026Article
- Single-cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease.bioRxiv : the preprint server for biology · 2026Article
- Single-cell full-length transcriptome of human lung reveals genetic effects on isoform regulation beyond gene-level expression.bioRxiv : the preprint server for biology · 2026Article
- Elucidating the coordination of RNA processing using short-read and long-read RNA-sequencing methods.Nature reviews. Molecular cell biology · 2026Review
- Allelic Variation at 9p21.3 Orchestrates Widespread RNA Splicing Shifts Governing Vascular Smooth Muscle Cell Plasticity.bioRxiv : the preprint server for biology · 2026Article
- Article
- Genetics of PLCG2 expression and splicing relative to Alzheimer's disease risk.Molecular neurodegeneration advances · 2026Article
- Long-Read Sequencing Reveals RNA Splicing Complexity in Human Diseases.Computational and structural biotechnology journal · 2026Review
- Microglia heterogeneity and therapeutic strategies in Parkinson's disease.Frontiers in immunology · 2026Review
- The "cutting edge" of non-canonical RNA splicing.Frontiers in molecular biosciences · 2026Review
- Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.Frontiers in nutrition · 2026Review
Corrections and comments
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Authors and funding
39 authors.
Jack HumphreyDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-6274-6620
Erica BrophyDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Roman KosoyDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Biao ZengDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Elena CocciaDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-9849-2423
Daniele MatteiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ashvin RaviDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Tatsuhiko NaitoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-2779-4600
Anastasia G EfthymiouDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Elisa NavarroDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Claudia De SanctisNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Victoria Flores-AlmazanDepartment of Pathology, Department of Artificial Intelligence & Human Health, Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Benjamin Z MullerDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0009-0004-9712-6378
Gijsje J L J SnijdersNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Amanda AllanDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alexandra MünchDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-9609-3277
Reta Birhanu KitataBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.ORCID http://orcid.org/0000-0002-8973-7679
Steven P KleopoulosDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Stathis ArgyriouDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Periklis MalakatesDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0009-0005-6248-8931
Konstantina PsychogyiouDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0009-0000-1849-1715
Zhiping ShaoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nancy FrancoeurDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0003-1798-3587
Chia-Feng TsaiBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Marina A GritsenkoBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.ORCID http://orcid.org/0000-0001-9992-9829
Matthew E MonroeBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.ORCID http://orcid.org/0000-0002-1210-7169
Vanessa L PaurusBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.ORCID http://orcid.org/0000-0002-8960-2926
Karl K WeitzBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.ORCID http://orcid.org/0000-0003-3453-1283
Tujin ShiBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Robert SebraDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0001-9267-2426
Tao LiuBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.ORCID http://orcid.org/0000-0001-9529-6550
Lot D de WitteNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-7235-9958
Alison M GoateDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-0576-2472
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Vahram HaroutunianNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0001-5860-2512
Gabriel E HoffmanDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-0957-0224
John F FullardDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0001-9874-2907
Panos Roussos *Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.ORCID http://orcid.org/0000-0002-4640-6239
Towfique Raj *Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. towfique.raj@mssm.edu.ORCID http://orcid.org/0000-0002-9355-5704
Funding
Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R01-AG054005Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R21-AG063130Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) U01-AG058635Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) U01-AG068880
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.
Indexed as
Alzheimer DiseaseMicrogliaParkinson DiseaseRNA SplicingAlternative SplicingBrainGene Expression RegulationGenetic Predisposition to DiseaseHumansProtein IsoformsSequence Analysis, RNAProtein Isoforms
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PMID
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.