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Cell. 2018 Nov 29;175(6):1679-1687.e7. doi: 10.1016/j.cell.2018.09.049. Epub 2018 Oct 18.

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

Collaborators (134)

Mitrovič M, Patsopoulos NA, Beecham AH, Dankowski T, Goris A, Dubois B, D'hooghe MB, Lemmens R, Van Damme P, Søndergaard HB, Sellebjerg F, Sorensen PS, Ullum H, Thørner LW, Werge T, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusik S, Gourraud PA, Andlauer TFM, Pongratz V, Buck D, Gasperi C, Bayas A, Heesen C, Kümpfel T, Linker R, Paul F, Stangel M, Tackenberg B, Bergh FT, Warnke C, Wiendl H, Wildemann B, Zettl U, Ziemann U, Tumani H, Gold R, Grummel V, Hemmer B, Knier B, Lill CM, Luessi F, Dardiotis E, Agliardi C, Barizzone N, Mascia E, Bernardinelli L, Comi G, Cusi D, Esposito F, Ferrè L, Comi C, Galimberti D, Leone MA, Sorosina M, Mescheriakova J, Hintzen R, van Duijn C, Theunissen CE, Bos SD, Myhr KM, Celius EG, Lie BA, Spurkland A, Comabella M, Montalban X, Alfredsson L, Stridh P, Hillert J, Jagodic M, Piehl F, Jelčić I, Martin R, Sospedra M, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Neville M, Santaniello A, Caillier SJ, Calabresi PA, Cree BAC, Cross A, Davis MF, Haines JL, de Bakker PIW, Delgado S, Dembele M, Edwards K, Fitzgerald KC, Hakonarson H, Konidari I, Lathi E, Manrique CP, Pericak-Vance MA, Piccio L, Schaefer C, McCabe C, Weiner H, Goldstein J, Olsson T, Hadjigeorgiou G, Taylor B, Tajouri L, Charlesworth J, Booth DR, Harbo HF, Ivinson AJ, Hauser SL, Compston A, Stewart G, Zipp F, Barcellos LF, Baranzini SE, Martinelli-Boneschi F, D'Alfonso S, Ziegler A, Oturai A, McCauley JL, Sawcer SJ, Oksenberg JR, De Jager PL, Kockum I, Hafler DA, Cotsapas C.

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.

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