Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
International Multiple Sclerosis Genetics Consortium (IMSGC) None., Beecham AH., Patsopoulos NA., Xifara DK., Davis MF., Kemppinen A., Cotsapas C., Shah TS., Spencer C., Booth D., Goris A., Oturai A., Saarela J., Fontaine B., Hemmer B., Martin C., Zipp F., D'Alfonso S., Martinelli-Boneschi F., Taylor B., Harbo HF., Kockum I., Hillert J., Olsson T., Ban M., Oksenberg JR., Hintzen R., Barcellos LF., Wellcome Trust Case Control Consortium 2 (WTCCC2) None., International IBD Genetics Consortium (IIBDGC) None., Agliardi C., Alfredsson L., Alizadeh M., Anderson C., Andrews R., Søndergaard HB., Baker A., Band G., Baranzini SE., Barizzone N., Barrett J., Bellenguez C., Bergamaschi L., Bernardinelli L., Berthele A., Biberacher V., Binder TMC., Blackburn H., Bomfim IL., Brambilla P., Broadley S., Brochet B., Brundin L., Buck D., Butzkueven H., Caillier SJ., Camu W., Carpentier W., Cavalla P., Celius EG., Coman I., Comi G., Corrado L., Cosemans L., Cournu-Rebeix I., Cree BAC., Cusi D., Damotte V., Defer G., Delgado SR., Deloukas P., di Sapio A., Dilthey AT., Donnelly P., Dubois B., Duddy M., Edkins S., Elovaara I., Esposito F., Evangelou N., Fiddes B., Field J., Franke A., Freeman C., Frohlich IY., Galimberti D., Gieger C., Gourraud P-A., Graetz C., Graham A., Grummel V., Guaschino C., Hadjixenofontos A., Hakonarson H., Halfpenny C., Hall G., Hall P., Hamsten A., Harley J., Harrower T., Hawkins C., Hellenthal G., Hillier C., Hobart J., Hoshi M., Hunt SE., Jagodic M., Jelčić I., Jochim A., Kendall B., Kermode A., Kilpatrick T., Koivisto K., Konidari I., Korn T., Kronsbein H., Langford C., Larsson M., Lathrop M., Lebrun-Frenay C., Lechner-Scott J., Lee MH., Leone MA., Leppä V., Liberatore G., Lie BA., Lill CM., Lindén M., Link J., Luessi F., Lycke J., Macciardi F., Männistö S., Manrique CP., Martin R., Martinelli V., Mason D., Mazibrada G., McCabe C., Mero I-L., Mescheriakova J., Moutsianas L., Myhr K-M., Nagels G., Nicholas R., Nilsson P., Piehl F., Pirinen M., Price SE., Quach H., Reunanen M., Robberecht W., Robertson NP., Rodegher M., Rog D., Salvetti M., Schnetz-Boutaud NC., Sellebjerg F., Selter RC., Schaefer C., Shaunak S., Shen L., Shields S., Siffrin V., Slee M., Sorensen PS., Sorosina M., Sospedra M., Spurkland A., Strange A., Sundqvist E., Thijs V., Thorpe J., Ticca A., Tienari P., van Duijn C., Visser EM., Vucic S., Westerlind H., Wiley JS., Wilkins A., Wilson JF., Winkelmann J., Zajicek J., Zindler E., Haines JL., Pericak-Vance MA., Ivinson AJ., Stewart G., Hafler D., Hauser SL., Compston A., McVean G., De Jager P., Sawcer SJ., McCauley JL.
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.