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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis
- Madireddy, Lohith;
- Patsopoulos, Niklaos A;
- Cotsapas, Chris;
- Bos, Steffan D;
- Beecham, Ashley;
- McCauley, Jacob;
- Kim, Kicheol;
- Jia, Xiaoming;
- Santaniello, Adam;
- Caillier, Stacy J;
- Andlauer, Till FM;
- Barcellos, Lisa F;
- Berge, Tone;
- Bernardinelli, Luisa;
- Martinelli-Boneschi, Filippo;
- Booth, David R;
- Briggs, Farren;
- Celius, Elisabeth G;
- Comabella, Manuel;
- Comi, Giancarlo;
- Cree, Bruce AC;
- D'Alfonso, Sandra;
- Dedham, Katrina;
- Duquette, Pierre;
- Efthimios, Dardiotis;
- Esposito, Federica;
- Fontaine, Bertrand;
- Gasperi, Christiane;
- Goris, An;
- Dubois, Benedicte;
- 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
Published Web Location
https://doi.org/10.1038/s41467-019-09773-yAbstract
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 intra-individual 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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