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

dc.contributor.authorMadireddy, L
dc.contributor.authorPatsopoulos, NA
dc.contributor.authorCotsapas, C
dc.contributor.authorBos, Steffan Daniel
dc.contributor.authorBeecham, Ashley
dc.contributor.authorMcCauley, J
dc.contributor.authorKim, K
dc.contributor.authorJia, X
dc.contributor.authorSantaniello, A
dc.contributor.authorCaillier, SJ
dc.contributor.authorAndlauer, TFM
dc.contributor.authorBarcellos, Lisa
dc.contributor.authorBerge, Tone
dc.contributor.authorBernardinelli, L
dc.contributor.authorMartinelli-Boneschi, F
dc.contributor.authorBooth, D
dc.contributor.authorBriggs, Farren
dc.contributor.authorCelius, Elisabeth Gulowsen
dc.contributor.authorComabella, M
dc.contributor.authorComi, G
dc.contributor.authorCree, BAC
dc.contributor.authorD'Alfonso, S
dc.contributor.authorDedham, K
dc.contributor.authorDuquette, P.
dc.contributor.authorDardiotis, E
dc.contributor.authorEsposito, F
dc.contributor.authorGasperi, Christiane
dc.contributor.authorGoris, A
dc.contributor.authorDubois, B
dc.contributor.authorGourraud, PA
dc.contributor.authorHadjigeorgiou, GM
dc.contributor.authorHaines, J
dc.contributor.authorHawkins, C
dc.contributor.authorHemmer, B
dc.contributor.authorHintzen, R
dc.contributor.authorHorakova, D
dc.contributor.authorIsobe, N
dc.contributor.authorKalra, S
dc.contributor.authorKira, Jun-ichi
dc.contributor.authorKhalil, M
dc.contributor.authorKockum, I
dc.contributor.authorLill, CM
dc.contributor.authorLincoln, Michelle
dc.contributor.authorLuessi, F
dc.contributor.authorMartin, R
dc.contributor.authorOturai, A
dc.contributor.authorPalotie, A
dc.contributor.authorPericak-Vance, MA
dc.contributor.authorHenry, R
dc.contributor.authorSaarela, J
dc.contributor.authorIvinson, Adrian
dc.contributor.authorOlsson, Thomas
dc.contributor.authorTaylor, Bruce
dc.contributor.authorStewart, GJ
dc.contributor.authorHarbo, Hanne Flinstad
dc.contributor.authorCompston, A
dc.contributor.authorHauser, SL
dc.contributor.authorHafler, DA
dc.contributor.authorZipp, F
dc.contributor.authorDe Jager, P
dc.contributor.authorSawcer, S
dc.contributor.authorOksenberg, JR
dc.contributor.authorBaranzini, SE
dc.date.accessioned2019-10-17T07:35:41Z
dc.date.accessioned2019-10-23T08:59:47Z
dc.date.available2019-10-17T07:35:41Z
dc.date.available2019-10-23T08:59:47Z
dc.date.issued2019-03-26
dc.identifier.citationMadireddy L, Patsopoulos N, Cotsapas C, Bos SD, Beecham A, McCauley J, Kim K, Jia X, Santaniello A, Caillier S, Andlauer, Barcellos L, Berge T, Bernardinelli L, Martinelli-Boneschi F, Booth D, Briggs F, Celius EG, Comabella M, Comi G, Cree B, D'Alfonso S, Dedham, Duquette P, Dardiotis E, Esposito F, Gasperi C, Goris A, Dubois B, Gourraud P, Hadjigeorgiou G, Haines J, Hawkins C, Hemmer B, Hintzen R, Horakova D, Isobe N, Kalra, Kira J, Khalil M, Kockum I, Lill C, Lincoln M, Luessi F, Martin R, Oturai A, Palotie A, Pericak-Vance M, Henry R, Saarela J, Ivinson A, Olsson T, Taylor B, Stewart G, Harbo HFH, Compston A, Hauser S, Hafler D, Zipp F, De Jager P, Sawcer S, Oksenberg J, Baranzini S. A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis.. Nature Communications. 2019;10en
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.urihttps://hdl.handle.net/10642/7767
dc.description.abstractGenome-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.en
dc.description.sponsorshipThis 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.en
dc.language.isoenen
dc.publisherNature Research (part of Springer Nature)en
dc.relation.ispartofseriesNature Communications;10, Article number: 2236 (2019)
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCellular signalling networksen
dc.subjectGenome informaticsen
dc.subjectGenome-wide association studiesen
dc.subjectMultiple sclerosisen
dc.titleA systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis.en
dc.typeJournal articleen
dc.typePeer revieweden
dc.date.updated2019-10-17T07:35:40Z
dc.description.versionupdatedVersionen
dc.identifier.doihttps://dx.doi.org/10.1038/s41467-019-09773-y
dc.identifier.cristin1737875
dc.source.journalNature Communications


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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Med mindre annet er angitt, så er denne innførselen lisensiert som This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.