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 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; 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. und Baranzini, Sergio E. (2019): A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis. In: Nature Communications, Bd. 10, 2236

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198