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Class II HLA interactions modulate genetic risk for multiple sclerosis

journal contribution
posted on 2023-05-18, 13:23 authored by Moutsianas, L, Jostins, L, Beecham, AH, Dilthey, AT, Xifara, DK, Ban, M, Shah, TS, Patsopoulos, NA, Alfredsson, L, Anderson, CA, Attfield, KE, Baranzini, SE, Barrett, J, Binder, TMC, Booth, D, Buck, D, Celius, EG, Cotsapas, C, D'Alfonso, S, Dendrou, CA, Donnelly, P, Dubois, B, Fontaine, B, Fugger, L, Goris, A, Gourraud, P-A, Graetz, C, Hemmer, B, Hillert, J, Kockum, I, Leslie, S, Lill, CM, Martinelli-Boneschi, F, Oksenberg, JR, Olsson, T, Oturai, A, Saarela, J, Sondergaard, HB, Spurkland, A, Bruce TaylorBruce Taylor, Winkelmann, J, Zipp, F, Haines, JL, Pericak-Vance, MA, Spencer, CCA, Stewart, G, Hafler, DA, Ivinson, AJ, Harbo, HF, Hauser, SL, De Jager, PL, Compston, A, McCauley, JL, Sawcer, S, McVean, G
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.

History

Publication title

Nature Genetics

Volume

47

Issue

10

Pagination

1107-1113

ISSN

1061-4036

Department/School

Menzies Institute for Medical Research

Publisher

Nature Publishing Group

Place of publication

345 Park Ave South, New York, USA, Ny, 10010-1707

Rights statement

Copyright 2015 Nature America

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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