Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

International Multiple Sclerosis Genetics Consortium

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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 languageEnglish
Pages (from-to)1679-1687.e7
JournalCell
Volume175
Issue number6
DOIs
Publication statusPublished - 29 Nov 2018

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Multiple Sclerosis
Genes
Genome-Wide Association Study
Linkage Disequilibrium
Regulatory T-Lymphocytes
Homeostasis
T-cells
Mutation

Cite this

International Multiple Sclerosis Genetics Consortium (2018). Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell, 175(6), 1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049
International Multiple Sclerosis Genetics Consortium. / Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. In: Cell. 2018 ; Vol. 175, No. 6. pp. 1679-1687.e7.
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International Multiple Sclerosis Genetics Consortium 2018, 'Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk' Cell, vol. 175, no. 6, pp. 1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049

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 journalArticleResearchpeer-review

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 - Agliardi, Cristina

AU - Barizzone, Nadia

AU - Mascia, Elisabetta

AU - Bernardinelli, Luisa

AU - Comi, Giancarlo

AU - Cusi, Daniele

AU - Esposito, Federica

AU - Ferrè, Laura

AU - Comi, Cristoforo

AU - Galimberti, Daniela

AU - Leone, Maurizio A.

AU - Sorosina, Melissa

AU - Mescheriakova, Julia

AU - Hintzen, Rogier

AU - van Duijn, Cornelia

AU - Theunissen, Charlotte E.

AU - Bos, Steffan D.

AU - Myhr, Kjell Morten

AU - Celius, Elisabeth G.

AU - Lie, Benedicte A.

AU - Spurkland, Anne

AU - Comabella, Manuel

AU - Montalban, Xavier

AU - Alfredsson, Lars

AU - Stridh, Pernilla

AU - Hillert, Jan

AU - Jagodic, Maja

AU - Piehl, Fredrik

AU - Jelčić, Ilijas

AU - Martin, Roland

AU - Sospedra, Mireia

AU - Ban, Maria

AU - Hawkins, Clive

AU - Hysi, Pirro

AU - Kalra, Seema

AU - Karpe, Fredrik

AU - Khadake, Jyoti

AU - Lachance, Genevieve

AU - Neville, Matthew

AU - Santaniello, Adam

AU - Caillier, Stacy J.

AU - Calabresi, Peter A.

AU - Cree, Bruce A.C.

AU - Cross, Anne

AU - Davis, Mary F.

AU - Haines, Jonathan L.

AU - de Bakker, Paul I.W.

AU - Delgado, Silvia

AU - Dembele, Marieme

AU - Edwards, Keith

AU - Fitzgerald, Kathryn C.

AU - Hakonarson, Hakon

AU - Konidari, Ioanna

AU - Lathi, Ellen

AU - Manrique, Clara P.

AU - Pericak-Vance, Margaret A.

AU - Piccio, Laura

AU - Schaefer, Cathy

AU - McCabe, Cristin

AU - Weiner, Howard

AU - Goldstein, Jacqueline

AU - Olsson, Tomas

AU - Hadjigeorgiou, Georgios

AU - Taylor, Bruce

AU - Tajouri, Lotti

AU - Charlesworth, Jac

AU - Booth, David R.

AU - Harbo, Hanne F.

AU - Ivinson, Adrian J.

AU - Hauser, Stephen L.

AU - Compston, Alastair

AU - Stewart, Graeme

AU - Zipp, Frauke

AU - Barcellos, Lisa F.

AU - Baranzini, Sergio E.

AU - Martinelli-Boneschi, Filippo

AU - D'Alfonso, Sandra

AU - Ziegler, Andreas

AU - Oturai, Annette

AU - McCauley, Jacob L.

AU - Sawcer, Stephen J.

AU - Oksenberg, Jorge R.

AU - De Jager, Philip L.

AU - Kockum, Ingrid

AU - Hafler, David A.

AU - Cotsapas, Chris

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

U2 - 10.1016/j.cell.2018.09.049

DO - 10.1016/j.cell.2018.09.049

M3 - Article

VL - 175

SP - 1679-1687.e7

JO - Cell

JF - Cell

SN - 0092-8674

IS - 6

ER -

International Multiple Sclerosis Genetics Consortium. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell. 2018 Nov 29;175(6):1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049