University Of Tasmania

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Low-frequency and rare-coding variation contributes to multiple sclerosis risk

journal contribution
posted on 2023-05-20, 00:40 authored by Mitrovic, M, Patsopoulos, NA, Beecham, AH, Dankowski, T, Goris, A, Dubois, B, D'hooghe, MB, Lemmens, R, Van Damme, P, Sondergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thorner, LW, Werge, T, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusik, S, Gourraud, P-A, Andlauer, TFM, Pongratz, V, Buck, D, Gasperi, C, Bayas, A, Heesen, C, Kumpfel, 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, Ferre, L, Comi, C, Galimberti, D, Leone, MA, Sorosina, M, Mescheriakova, J, Hintzen, R, van Duijn, C, Theunissen, CE, Bos, SD, Myhr, K-M, Celius, EG, Lie, BA, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Stridh, P, Hillert, J, Jagodic, M, Piehl, F, Jelcic, 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, Bruce TaylorBruce Taylor, Tajouri, L, Jac CharlesworthJac Charlesworth, 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
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.


National Health & Medical Research Council


Publication title











Menzies Institute for Medical Research


Cell Press

Place of publication

1100 Massachusetts Ave, Cambridge, USA, Ma, 02138

Rights statement

Copyright 2018 The Author

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  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified; Clinical health not elsewhere classified