A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis
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. ; This investigation was supported in part by the following sources: NIH/NINDS awards R01NS088155 and 1R01NS099240, the Valhalla Charitable Foundation, and the Heidrich Family and Friends Foundation (Sergio E. Baranzini). US National Multiple Sclerosis Society (TA 3056-A-2), the Harvard NeuroDiscovery Center and an Intel Parallel Computing Center award (Nikolaos A. Patsopoulos). Swedish Medical Research Council; Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA insurance, Swedish Brain Foundation, the Swedish Association for Persons with Neurological Disabilities. Cambridge NIHR Biomedical Research Centre, UK Medical Research Council (G1100125) and the UK MS society (861/07). NIH/NINDS: R01 NS049477, NIH/NIAID: R01 AI059829, NIH/NIEHS: R01 ES0495103. Research Council of Norway grant 196776 and 240102. NINDS/NIH R01NS088155. Oslo MS association. Research Council KU Leuven, Research Foundation Flanders. AFM, AFM-Généthon, CIC, ARSEP, ANR-10-INBS-01 and ANR-10-IAIHU-06. Research Council KU Leuven, Research Foundation Flanders. Inserm ATIP-Avenir Fellowship and Connect-Talents Award. German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Oslo MS association, Research Council of Norway grant 196776 and 240102. Dutch MS Research Foundation. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Italian Foundation of Multiple Sclerosis (FISM). NMSS (RG 4680A1/1). German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Lundbeck Foundation and Benzon Foundation. ; updatedVersion