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

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

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

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 MalakatesKonstantina 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	1610
Journal	Nature Genetics
DOIs	https://doi.org/10.1038/s41588-025-02099-0
State	Accepted/In press - 2025

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Humphrey, J., Brophy, E., Kosoy, R., Zeng, B., Coccia, E., Mattei, D., Ravi, A., Naito, T., Efthymiou, A. G., Navarro, E., De Sanctis, C., Flores-Almazan, V., Muller, B. Z., Snijders, G. J. L. J., Allan, A., Münch, A., Kitata, R. B., Kleopoulos, S. P., Argyriou, S., ... Raj, T. (Accepted/In press). Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing. Nature Genetics, Article 1610. https://doi.org/10.1038/s41588-025-02099-0

@article{f2c04b0bedaa4ffbac0ab4340f13aaf0,

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

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{\textquoteright}s and Parkinson{\textquoteright}s disease. We nominate several loci that may act through complex changes in isoform and splice-site usage.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

doi = "10.1038/s41588-025-02099-0",

language = "English",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

}

Humphrey, J, Brophy, E, Kosoy, R, Zeng, B, Coccia, E, Mattei, D, Ravi, A, Naito, T, Efthymiou, AG, Navarro, E, De Sanctis, C, Flores-Almazan, V, Muller, BZ, Snijders, GJLJ, Allan, A, Münch, A, Kitata, RB, Kleopoulos, SP, Argyriou, S, Malakates, P, Psychogyiou, K, Shao, Z, Francoeur, N, Tsai, CF, Gritsenko, MA, Monroe, ME, Paurus, VL, Weitz, KK, Shi, T, Sebra, R, Liu, T, de Witte, LD , Goate, AM, Bennett, DA, Haroutunian, V , Hoffman, GE , Fullard, JF , Roussos, P & Raj, T 2025, 'Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing', Nature Genetics. https://doi.org/10.1038/s41588-025-02099-0

TY - JOUR

T1 - Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing

AU - Humphrey, Jack

AU - Brophy, Erica

AU - Kosoy, Roman

AU - Zeng, Biao

AU - Coccia, Elena

AU - Mattei, Daniele

AU - Ravi, Ashvin

AU - Naito, Tatsuhiko

AU - Efthymiou, Anastasia G.

AU - Navarro, Elisa

AU - De Sanctis, Claudia

AU - Flores-Almazan, Victoria

AU - Muller, Benjamin Z.

AU - Snijders, Gijsje J.L.J.

AU - Allan, Amanda

AU - Münch, Alexandra

AU - Kitata, Reta Birhanu

AU - Kleopoulos, Steven P.

AU - Argyriou, Stathis

AU - Malakates, Periklis

AU - Psychogyiou, Konstantina

AU - Shao, Zhiping

AU - Francoeur, Nancy

AU - Tsai, Chia Feng

AU - Gritsenko, Marina A.

AU - Monroe, Matthew E.

AU - Paurus, Vanessa L.

AU - Weitz, Karl K.

AU - Shi, Tujin

AU - Sebra, Robert

AU - Liu, Tao

AU - de Witte, Lot D.

AU - Goate, Alison M.

AU - Bennett, David A.

AU - Haroutunian, Vahram

AU - Hoffman, Gabriel E.

AU - Fullard, John F.

AU - Roussos, Panos

AU - Raj, Towfique

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=86000209585&partnerID=8YFLogxK

U2 - 10.1038/s41588-025-02099-0

DO - 10.1038/s41588-025-02099-0

M3 - Article

C2 - 40033057

AN - SCOPUS:86000209585

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

M1 - 1610

ER -

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

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