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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

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Madireddy, Lohith | Patsopoulos, Nikolaos, A | Cotsapas, Chris | Bos, Steffan, D | Beecham, Ashley | Mccauley, Jacob | Kim, Kicheol | Jia, Xiaoming | Santaniello, Adam | Caillier, Stacy, J | Andlauer, Till, F M | Barcellos, Lisa, F | Berge, Tone | Bernardinelli, Luisa | Martinelli-Boneschi, Filippo | Booth, David, R | Briggs, Farren | Celius, Elisabeth, G | Comabella, Manuel | Comi, Giancarlo | Cree, Bruce, a C | D’alfonso, Sandra | Dedham, Katrina | Duquette, Pierre | Dardiotis, Efthimios | Esposito, Federica | Fontaine, Bertrand | Gasperi, Christiane | Goris, An | Dubois, Bénédicte | Gourraud, Pierre-Antoine | Hadjigeorgiou, Georgios | Haines, Jonathan | Hawkins, Clive | Hemmer, Bernhard | Hintzen, Rogier | Horakova, Dana | Isobe, Noriko | Kalra, Seema | Kira, Jun-Ichi | Khalil, Michael | Kockum, Ingrid | Lill, Christina, M | Lincoln, Matthew, R | Luessi, Felix | Martin, Roland | Oturai, Annette | Palotie, Aarno | Pericak-Vance, Margaret, A | Henry, Roland | Saarela, Janna | Ivinson, Adrian | Olsson, Tomas | Taylor, Bruce, V | Stewart, Graeme, J | Harbo, Hanne, F | Compston, Alastair | Hauser, Stephen, L | Hafler, David, A | Zipp, Frauke | de Jager, Philip | Sawcer, Stephen | Oksenberg, Jorge, R | Baranzini, Sergio, E

Edité par CCSD ; Nature Publishing Group -

International audience. International Multiple Sclerosis Genetics Consortium Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intraindividual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

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