The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility
Authors:   International Multiple Sclerosis Genetics Consortium, Patsopoulos NA , Baranzini SE , Santaniello A , Shoostari P , Cotsapas C , Wong G , Beecham AH , James T , Replogle J , Vlachos I , McCabe C , Pers T , Brandes A , White C , Keenan B , Cimpean M , Winn P , Panteliadis IP , Robbins A , Andlauer TFM , Zarzycki O , Dubois B , Goris A , Sondergaard H Bach , Sellebjerg F , Sorensen P Soelberg , Ullum H , Thoerner L Wegner , Saarela J , Rebeix I Cournu , Damotte V , Fontaine B , Noel L Guillot , Lathrop M , Vukusik S , Berthele A , Biberacher V , Buck D , Gasperi C , Graetz C , Grummel V , Hemmer B , Hoshi M , Knier B , Korn T , Lill CM , Luessi F , Mühlau M , Zipp F , Dardiotis E , Agliardi C , Amoroso A , Barizzone N , Benedetti MD , Bernardinelli L , Cavalla P , Clarelli F , Comi G , Cusi D , Esposito F , Ferrè L , Galimberti D , Guaschino C , Leone MA , Martinelli V , Moiola L , Salvetti M , Sorosina M , Vecchio D , Zauli A , Santoro S , Zuccalà M , Mescheriakova J , Duijn C van , Bos SD , Celius EG , Spurkland A , Comabella M , Montalban X , Alfredsson L , Bomfim I , Gomez-Cabrero D , Hillert J , Jagodic M , Lindén M , Piehl F , Jelčić I , Martin R , Sospedra M , Baker A , Ban M , Hawkins C , Hysi P , Kalra S , Karpe F , Khadake J , Lachance G , Molyneux P , Neville M , Thorpe J , Bradshaw E , Caillier SJ , Calabresi P , Cree BAC , Cross A , Davis M , Bakker PWI de , Delgado S , Dembele M , Edwards K , Fitzgerald K , Frohlich IY , Gourraud PA , Haines JL , Hakonarson H , Kimbrough D , Isobe N , Konidari I , Lathi E , Lee MH , Li T , An D , Zimmer A , Lo A , Madireddy L , Manrique CP , Mitrovic M , Olah M , Patrick E , Pericak-Vance MA , Piccio L , Schaefer C , Weiner H , Lage K , Compston A , Hafler D , Harbo HF , Hauser SL , Stewart G , D’Alfonso S , Hadjigeorgiou G , Taylor B , Barcellos LF , Booth D , Hintzen R , Kockum I , Martinelli-Boneschi F , McCauley JL , Oksenberg JR , Oturai A , Sawcer S , Ivinson AJ , Olsson T , Jager PL De , Barclay Murray , Peyrin-Biroulet Laurent , Chamaillard Mathias , Colombe Jean-Frederick , Cottone Mario , Croft Anthony , D’Incà Renata , Halfvarson Jonas , Hanigan Katherine , Henderson Paul , Hugot Jean-Pierre , Karban Amir , Kennedy Nicholas A , Khan Mohammed Azam , Lémann Marc , Levine Arie , Massey Dunecan , Milla Monica , Montgomery Grant W , Evelyn Ng Sok Meng , Oikonomou Ioannis , Peeters Harald , Proctor Deborah D. , Rahier Jean-Francois , Roberts Rebecca , Rutgeerts Paul , Seibold Frank , Stronati Laura , Taylor Kirstin M , Törkvist Leif , Ublick Kullak , Limbergen Johan Van , Gossum Andre Van , Vatn Morten H. , Zhang Hu , Zhang Wei ,   Australia and New Zealand IBDGC,   Belgium Genetic Consortium,   Initiative on Crohn and Colitis,   NIDDK IBDGC,   United Kingdom IBDGC,   Wellcome Trust Case Control Consortium
Published: July 2017

Abstract:We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.One Sentence Summary:We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.