Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets
Abstract 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 uti...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Genome Biology |
| Online Access: | https://doi.org/10.1186/s13059-022-02694-y |
| _version_ | 1828215433733341184 |
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| author | Michael H. Guo Prashanth Sama Brenna A. LaBarre Hrishikesh Lokhande John Balibalos Ci Chu Xiaomi Du Pouya Kheradpour Charles C. Kim Taylor Oniskey Thomas Snyder Damien Z. Soghoian Howard L. Weiner Tanuja Chitnis Nikolaos A. Patsopoulos |
| author_facet | Michael H. Guo Prashanth Sama Brenna A. LaBarre Hrishikesh Lokhande John Balibalos Ci Chu Xiaomi Du Pouya Kheradpour Charles C. Kim Taylor Oniskey Thomas Snyder Damien Z. Soghoian Howard L. Weiner Tanuja Chitnis Nikolaos A. Patsopoulos |
| author_sort | Michael H. Guo |
| collection | DOAJ |
| description | Abstract 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 Th17 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. |
| first_indexed | 2024-04-12T15:20:51Z |
| format | Article |
| id | doaj.art-b853f835c3b7425b97ee266ce7fa4c92 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-04-12T15:20:51Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-b853f835c3b7425b97ee266ce7fa4c922022-12-22T03:27:28ZengBMCGenome Biology1474-760X2022-06-0123112310.1186/s13059-022-02694-yDissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsetsMichael H. Guo0Prashanth Sama1Brenna A. LaBarre2Hrishikesh Lokhande3John Balibalos4Ci Chu5Xiaomi Du6Pouya Kheradpour7Charles C. Kim8Taylor Oniskey9Thomas Snyder10Damien Z. Soghoian11Howard L. Weiner12Tanuja Chitnis13Nikolaos A. Patsopoulos14Department of Neurology, Perelman School of Medicine, University of PennsylvaniaBroad Institute of Harvard and Massachusetts Institute of TechnologyBroad Institute of Harvard and Massachusetts Institute of TechnologyBrigham Multiple Sclerosis Center, Brigham and Women’s HospitalVerily Life SciencesVerily Life SciencesVerily Life SciencesVerily Life SciencesVerily Life SciencesVerily Life SciencesVerily Life SciencesVerily Life SciencesBrigham Multiple Sclerosis Center, Brigham and Women’s HospitalBrigham Multiple Sclerosis Center, Brigham and Women’s HospitalBroad Institute of Harvard and Massachusetts Institute of TechnologyAbstract 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 Th17 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.https://doi.org/10.1186/s13059-022-02694-y |
| spellingShingle | Michael H. Guo Prashanth Sama Brenna A. LaBarre Hrishikesh Lokhande John Balibalos Ci Chu Xiaomi Du Pouya Kheradpour Charles C. Kim Taylor Oniskey Thomas Snyder Damien Z. Soghoian Howard L. Weiner Tanuja Chitnis Nikolaos A. Patsopoulos Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets Genome Biology |
| 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 |
| url | https://doi.org/10.1186/s13059-022-02694-y |
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