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Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets
BACKGROUND: Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. RESULTS: We utilize ch...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175345/ https://www.ncbi.nlm.nih.gov/pubmed/35672799 http://dx.doi.org/10.1186/s13059-022-02694-y |
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author | Guo, Michael H. Sama, Prashanth LaBarre, Brenna A. Lokhande, Hrishikesh Balibalos, John Chu, Ci Du, Xiaomi Kheradpour, Pouya Kim, Charles C. Oniskey, Taylor Snyder, Thomas Soghoian, Damien Z. Weiner, Howard L. Chitnis, Tanuja Patsopoulos, Nikolaos A. |
author_facet | Guo, Michael H. Sama, Prashanth LaBarre, Brenna A. Lokhande, Hrishikesh Balibalos, John Chu, Ci Du, Xiaomi Kheradpour, Pouya Kim, Charles C. Oniskey, Taylor Snyder, Thomas Soghoian, Damien Z. Weiner, Howard L. Chitnis, Tanuja Patsopoulos, Nikolaos A. |
author_sort | Guo, Michael H. |
collection | PubMed |
description | BACKGROUND: Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. RESULTS: We utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to T(h)17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. CONCLUSIONS: Overall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02694-y. |
format | Online Article Text |
id | pubmed-9175345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-91753452022-06-09 Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets Guo, Michael H. Sama, Prashanth LaBarre, Brenna A. Lokhande, Hrishikesh Balibalos, John Chu, Ci Du, Xiaomi Kheradpour, Pouya Kim, Charles C. Oniskey, Taylor Snyder, Thomas Soghoian, Damien Z. Weiner, Howard L. Chitnis, Tanuja Patsopoulos, Nikolaos A. Genome Biol Research BACKGROUND: Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. RESULTS: We utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to T(h)17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. CONCLUSIONS: Overall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02694-y. BioMed Central 2022-06-07 /pmc/articles/PMC9175345/ /pubmed/35672799 http://dx.doi.org/10.1186/s13059-022-02694-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Guo, Michael H. Sama, Prashanth LaBarre, Brenna A. Lokhande, Hrishikesh Balibalos, John Chu, Ci Du, Xiaomi Kheradpour, Pouya Kim, Charles C. Oniskey, Taylor Snyder, Thomas Soghoian, Damien Z. Weiner, Howard L. Chitnis, Tanuja Patsopoulos, Nikolaos A. Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets |
title | Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets |
title_full | Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets |
title_fullStr | Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets |
title_full_unstemmed | Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets |
title_short | Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets |
title_sort | dissection of multiple sclerosis genetics identifies b and cd4+ t cells as driver cell subsets |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175345/ https://www.ncbi.nlm.nih.gov/pubmed/35672799 http://dx.doi.org/10.1186/s13059-022-02694-y |
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