Class II HLA interactions modulate genetic risk for multiple sclerosis.

Loukas Moutsianas, Luke Jostins, Ashley H Beecham, Alexander T Dilthey, Dionysia K Xifara, Maria Ban, Tejas S Shah, Nikolaos A Patsopoulos, Lars Alfredsson, Carl A Anderson, Katherine E Attfield, Sergio E Baranzini, Jeffrey Barrett, Thomas M C Binder, David Booth, Dorothea Buck, Elisabeth G Celius, Chris Cotsapas, Sandra D'Alfonso, Calliope A Dendrou, Peter Donnelly, Bénédicte Dubois, Bertrand Fontaine, Lars Lar Fugger, An Goris, Pierre-Antoine Gourraud, Christiane Graetz, Bernhard Hemmer, Jan Hillert, - -, Ingrid Kockum, Stephen Leslie, Christina M Lill, Filippo Martinelli-Boneschi, Jorge R Oksenberg, Tomas Olsson, Annette Oturai, Janna Saarela, Helle Bach Søndergaard, Anne Spurkland, Bruce Taylor, Juliane Winkelmann, Frauke Zipp, Jonathan L Haines, Margaret A Pericak-Vance, Chris C A Spencer, Graeme Stewart, David A Hafler, Adrian J Ivinson, Hanne F Harbo, Stephen L Hauser, Philip L De Jager, Alastair Compston, Jacob L McCauley, Stephen wcer Sawcer, Gil McVean
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Nature genetics
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Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.