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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, CMultiple 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.
Funding
National Health & Medical Research Council
History
Publication title
CellVolume
175Issue
6Pagination
1679-1687ISSN
0092-8674Department/School
Menzies Institute for Medical ResearchPublisher
Cell PressPlace of publication
1100 Massachusetts Ave, Cambridge, USA, Ma, 02138Rights statement
Copyright 2018 The AuthorRepository Status
- Restricted