Abstract
Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
Original language | English (US) |
---|---|
Pages (from-to) | 1679-1687.e7 |
Journal | Cell |
Volume | 175 |
Issue number | 6 |
DOIs | |
State | Published - Nov 29 2018 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. / International Multiple Sclerosis Genetics Consortium.
In: Cell, Vol. 175, No. 6, 29.11.2018, p. 1679-1687.e7.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk
AU - International Multiple Sclerosis Genetics Consortium
AU - Mitrovič, Mitja
AU - Patsopoulos, Nikolaos A.
AU - Beecham, Ashley H.
AU - Dankowski, Theresa
AU - Goris, An
AU - Dubois, Bénédicte
AU - D'hooghe, Marie B.
AU - Lemmens, Robin
AU - Van Damme, Philip
AU - Søndergaard, Helle Bach
AU - Sellebjerg, Finn
AU - Sorensen, Per Soelberg
AU - Ullum, Henrik
AU - Thørner, Lise W.
AU - Werge, Thomas
AU - Saarela, Janna
AU - Cournu-Rebeix, Isabelle
AU - Damotte, Vincent
AU - Fontaine, Bertrand
AU - Guillot-Noel, Lena
AU - Lathrop, Mark
AU - Vukusik, Sandra
AU - Gourraud, Pierre Antoine
AU - Andlauer, Till F.M.
AU - Pongratz, Viola
AU - Buck, Dorothea
AU - Gasperi, Christiane
AU - Bayas, Antonios
AU - Heesen, Christoph
AU - Kümpfel, Tania
AU - Linker, Ralf
AU - Paul, Friedemann
AU - Stangel, Martin
AU - Tackenberg, Björn
AU - Bergh, Florian Then
AU - Warnke, Clemens
AU - Wiendl, Heinz
AU - Wildemann, Brigitte
AU - Zettl, Uwe
AU - Ziemann, Ulf
AU - Tumani, Hayrettin
AU - Gold, Ralf
AU - Grummel, Verena
AU - Hemmer, Bernhard
AU - Knier, Benjamin
AU - Lill, Christina M.
AU - Luessi, Felix
AU - Dardiotis, Efthimios
AU - Calabresi, Peter A.
AU - Fitzgerald, Kathryn C.
N1 - Funding Information: Sandra Vukusic has received consulting and lecturing fees, travel grants and unconditional research support from Biogen Idec, Geneuro, Genzyme, MedDay, Merck Serono, Novartis, Roche, Sanofi Aventis and Teva Pharma. Funding Information: Heinz Wiendl receives honoraria for acting as a member of Scientific Advisory Boards and as consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Prof. Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen GmbH, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme. Funding Information: Brigitte Wildemann has received grants from the German Ministry of Education and Research, grants from Dietmar Hopp Founfation, grants from Klaus Tschira Foundation, personal fees from Bayer Healthcare, personal fees from Biogen Idec, grants and personal fees from Merck Serono, grants and personal fees from Novartis, grants and personal fees from Sanofi Genzyme, grants and personal fees from TEVA, outside the submitted work. Funding Information: Behring, Genzyme, Merck Serono, Novartis, Roche, Stendhal, Talecris, and TEVA. His department received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis, TEVA. He possesses stock options from Merck Serono and Roche. Funding Information: Hanne F Harbo has received travel support and honoraria from Biogen Idec, Sanofi-Genzyme, Merck, Novartis, Roche, and Teva and an unrestricted research grant from Novartis. Funding Information: Elizabeth G Celius has received personal compensation for serving on scientific advisory boards for Almirall, Biogen Idec, Merck, Novartis, Genzyme and Teva, has received speaker honoraria from Biogen Idec, Genzyme, Novartis, Merck and Teva, and her department has received unrestricted research grants from Novartis and Genzyme. Funding Information: Friedemann Paul has received honoraria and research support from Alexion, Bayer, Biogen Idec, Chugai, MerckSerono, Novartis, Genyzme, MedImmune, Shire, Teva, and serves on scientific advisory boards for Alexion, MedImmune and Novartis. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis), Guthy Jackson Charitable Foundation, EU Framework Program 7, National Multiple Sclerosis Society of the USA, and serves on advisory boards and steering committees for Novartis and MedImmune. Funding Information: Sample collection and genotyping was supported by NHMRC project grant APP605511.B.D., R.L., and P.V.D. are Clinical Investigators of the Research Foundation Flanders (FWO-Vlaanderen). A.G. and B.D. are supported by the Research Fund KU Leuven (C24/16/045) and the Research Foundation Flanders (FWO-Vlaanderen) (G.0734.15). The SiGN study was funded by a cooperative agreement grant from the US National Institute of Neurological Disorders and Stroke, National Institutes of Health (U01-NS069208).We would like to thank Verena Grummel and Nadine Miksch for technical support. We thank Sabine Fleischer for continuous and extensive support with biobanking logistics. This work was supported by the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” [KKNMS]) [01GI0916, 01GI0917] and the Munich Cluster for Systems Neurology (SyNergy). The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The popgen 2.0 network is supported by a grant from the German Ministry for Education and Research (01EY1103). The Heinz Nixdorf Recall Study was supported by the Heinz Nixdorf Foundation Germany, the BMBF, and the Deutsche Forschungsgemeinschaft (DFG; ER 155/6-1, ER 155/6-2).Sample collection and genotyping was supported by the Italian Foundation for Multiple Sclerosis (FISM grants, special project “Immunochip” 2011/R/1, 2015/R/10) and Fondazione Cariplo (grant 2010-0728).The Norwegian MS and control samples were collected and funded in collaboration between the multiple sclerosis research group in at Oslo University Hospital/University in Oslo, the Norwegian MS Registry and Biobank in Bergen, and the Norwegian Bone Marrow Registry, supported by the Oslo MS Association, Bergen MS Society, Odda MS Society, and the Research Council of Norway (grant 240102_Harbo).Sample collection and genotyping was supported by the 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; and AstraZeneca Science for Life grant.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 National Institute for Health Research (NIHR) Biomedical Research Centre, UK Medical Research Council (G1100125) and the UK MS Society (861/07). We thank the NIHR and NHS Blood and Transplant. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, and the NIHR-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St. Thomas's NHS Foundation Trust in partnership with King's College London. We thank the volunteers from the Oxford Biobank (https://www.oxfordbiobank.org.uk/) for their participation. The recall process was supported by the NIHR Oxford Biomedical Research Centre Programme. The recall process was supported by the NIHR Oxford Biomedical Research Centre Programme. We thank Neil Robertson, Sam Loveless, Richard Reynolds, and John Zajicek for contributing case samples from the UK. The study makes use of material from the UK MS Society Tissue Bank (grant no 910/09) provided by Richard Reynolds.We thank the Biorepository Facility and the Center for Genome Technology laboratory personnel (specifically Sandra West, Simone Clarke, Daniela Martinez, and Patrice Whitehead) within the John P. Hussman Institute for Human Genomics at the University of Miami for centralized DNA handling and genotyping for this project. Related funding support is from the US National Multiple Sclerosis Society (grant RG-4680-A-1) and the NIH (R01-NS096212, R01-NS049477, and R01-NS026799). The IMSGC wishes to acknowledge William and Lois Edgerly, John and Elaine Carlos, Martha Crowninshield, and William and Cindy Fowler, whose enduring committments were critical in creation of the consortium. Funding Information: Bénédicte Dubois and An Goris have received travel/consulting fees and/or research funding from Novartis, Merck-Serono and Roche. B.D. has received consulting fees and/or funding from Biogen Idec, Sanofi-Aventis and Teva Publisher Copyright: © 2018 The Author
PY - 2018/11/29
Y1 - 2018/11/29
N2 - Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
AB - Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
UR - http://www.scopus.com/inward/record.url?scp=85059424484&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059424484&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.09.049
DO - 10.1016/j.cell.2018.09.049
M3 - Article
C2 - 30343897
AN - SCOPUS:85059424484
VL - 175
SP - 1679-1687.e7
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -