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 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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
}
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
AU - Fitzgerald, Kathryn
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 -