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

Mitrovi, 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, PA, 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, Taylor, B, Tajouri, L, Charlesworth, J ORCID: 0000-0001-6201-3518, 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 and Cotsapas, C 2018 , 'Low-frequency and rare-coding variation contributes to multiple sclerosis risk' , Cell, vol. 175, no. 6 , pp. 1679-1687 , doi: 10.1016/j.cell.2018.09.049.

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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.

Item Type: Article
Authors/Creators:Mitrovi, M and Patsopoulos, NA and Beecham, AH and Dankowski, T and Goris, A and Dubois, B and D'hooghe, MB and Lemmens, R and Van Damme, P and Sondergaard, HB and Sellebjerg, F and Sorensen, PS and Ullum, H and Thorner, LW and Werge, T and Saarela, J and Cournu-Rebeix, I and Damotte, V and Fontaine, B and Guillot-Noel, L and Lathrop, M and Vukusik, S and Gourraud, PA and Andlauer, TFM and Pongratz, V and Buck, D and Gasperi, C and Bayas, A and Heesen, C and Kumpfel, T and Linker, R and Paul, F and Stangel, M and Tackenberg, B and Bergh, FT and Warnke, C and Wiendl, H and Wildemann, B and Zettl, U and Ziemann, U and Tumani, H and Gold, R and Grummel, V and Hemmer, B and Knier, B and Lill, CM and Luessi, F and Dardiotis, E and Agliardi, C and Barizzone, N and Mascia, E and Bernardinelli, L and Comi, G and Cusi, D and Esposito, F and Ferre, L and Comi, C and Galimberti, D and Leone, MA and Sorosina, M and Mescheriakova, J and Hintzen, R and van Duijn, C and Theunissen, CE and Bos, SD and Myhr, K-M and Celius, EG and Lie, BA and Spurkland, A and Comabella, M and Montalban, X and Alfredsson, L and Stridh, P and Hillert, J and Jagodic, M and Piehl, F and Jelcic, I and Martin, R and Sospedra, M and Ban, M and Hawkins, C and Hysi, P and Kalra, S and Karpe, F and Khadake, J and Lachance, G and Neville, M and Santaniello, A and Caillier, SJ and Calabresi, PA and Cree, BAC and Cross, A and Davis, MF and Haines, JL and de Bakker, PIW and Delgado, S and Dembele, M and Edwards, K and Fitzgerald, KC and Hakonarson, H and Konidari, I and Lathi, E and Manrique, CP and Pericak-Vance, MA and Piccio, L and Schaefer, C and McCabe, C and Weiner, H and Goldstein, J and Olsson, T and Hadjigeorgiou, G and Taylor, B and Tajouri, L and Charlesworth, J and Booth, DR and Harbo, HF and Ivinson, AJ and Hauser, SL and Compston, A and Stewart, G and Zipp, F and Barcellos, LF and Baranzini, SE and Martinelli-Boneschi, F and D'Alfonso, S and Ziegler, A and Oturai, A and McCauley, JL and Sawcer, SJ and Oksenberg, JR and De Jager, PL and Kockum, I and Hafler, DA and Cotsapas, C
Keywords: multiple sclerosis, genomics, rare variants, exome
Journal or Publication Title: Cell
Publisher: Cell Press
ISSN: 0092-8674
DOI / ID Number: 10.1016/j.cell.2018.09.049
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Copyright 2018 The Author

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