Journal article

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Nikolas A Patsopoulos, Sergio E Baranzini, Adams Santaniello, Parisa Shoostari, Chris Cotsapas, Garrett Wong, Ashley H Beecham, Tojo James, Joseph Replogle, Ioannis S Vlachos, Cristin McCabe, Tune H Pers, Aaron Brandes, Charles White, Brendan Keenan, Maria Cimpean, Phoebe Winn, Ioannis-Pavlos Panteliadis, Allison Robbins, Till FM Andlauer Show all



We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeti..

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Awarded by National MS Society (NMSS)

Awarded by NMSS

Awarded by NIH

Awarded by National Multiple Sclerosis Society

Awarded by U.S. National Multiple Sclerosis Society

Awarded by NIH/NINDS

Awarded by e:Med Programme

Awarded by Wellcome Trust Case Control Consortium 2 project

Awarded by Medical Research Council

Awarded by Wellcome Trust

Awarded by UK Medical Research Council

Awarded by UK MS society

Awarded by NIH/NIAID

Awarded by NIH/NIEHS

Awarded by Research Council of Norway

Awarded by NINDS/NIH

Awarded by Italian Foundation of Multiple Sclerosis (FISM)

Awarded by Danish Council for Strategic Research

Awarded by French government


Funding Acknowledgements

This investigation was supported in part by grants from the National MS Society (NMSS) to A.J.I. on behalf of the International MS Genetics Consortium (RG 4198-A-1 and AP-3758-A-16). Other grants include a Harry Weaver Neuroscience Scholar Award from the NMSS to P.L.D. (JF2138A1) as well as NIH grants RC2 GM093080 and R01AG036836. This work was also supported by a postdoctoral fellowship from the National Multiple Sclerosis Society (FG 1938-A-1) and a Career Independence Award from the National Multiple Sclerosis Society (TA 3056-A-2) to N.A.P. and National Multiple Sclerosis Society award AP3758-A-16. N.A.P. has been supported by Harvard Neuro Discovery Center and an Intel Parallel Computing Center award, the U.S. National Multiple Sclerosis Society (grants RG 4680-A-1), and the NIH/NINDS (grant R01NS096212). T.A. was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J), Swedish Medical Research Council; Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA insurance, Swedish Brain Foundation, and the Swedish Association for Persons with Neurological Disabilities. This study makes use of data generated as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), including data from the British 1958 Birth Cohort DNA collection (funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02) and the UK National Blood Service controls (funded by the Wellcome Trust). The study was supported by the 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 and the Norwegian MS Registry and Biobank and the Norwegian Bone Marrow Registry; Research Council KU Leuven, Research Foundation Flanders; AFM, AFM-Genethon, 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); and Dutch MS Research Foundation. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust in partnership with Kings College London. The recall process was supported by the NIHR Oxford Biomedical Research Centre Programme; Italian Foundation of Multiple Sclerosis (FISM grants, Special Project Immunochip 2011/R/1, 2015/R/10); NMSS (RG 4680A1/1); and the MultipleMS EU project. We acknowledge the Lundbeck Foundation and Benzon Foundation for support (THP). This research was supported by grants from the Danish Multiple Sclerosis Society, the Danish Council for Strategic Research [grant 2142-08-0039], Novartis, Biogen (Denmark) A/S, the Sofus Carl Emil Friis og Hustru Olga Doris Friis Foundation, and the Foundation for Research in Neurology.r The Observatoire Francais de la Sclerose en Plaques (OFSEP) is supported by a grant provided by the French government and handled by the Agence Nationale de la Recherche, within the framework of the Investments for the Future program, under the reference ANR-10-COHO-002, by the Eugene Devic EDMUS Foundation against multiple sclerosis, and by the ARSEP Foundation.