PT  - JOURNAL ARTICLE
AU  - Guhan Ram Venkataraman
AU  - Julia Eve Olivieri
AU  - Christopher DeBoever
AU  - Yosuke Tanigawa
AU  - Johanne Marie Justesen
AU  - Alexander Dilthey
AU  - Manuel A. Rivas
TI  - Pervasive additive and non-additive effects within the HLA region contribute to disease risk in the UK Biobank
AID  - 10.1101/2020.05.28.119669
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.28.119669
4099  - http://biorxiv.org/content/early/2020/06/12/2020.05.28.119669.short
4100  - http://biorxiv.org/content/early/2020/06/12/2020.05.28.119669.full
AB  - The human leukocyte antigen (HLA) region is one of the most disease-associated regions of the human genome, yet even well-studied alleles in the HLA region have unknown impact on disease. Here, we study the effect of 156 HLA alleles on 677 binary phenotypes for 337,138 individuals in the UK Biobank. We assess HLA allele associations and subsequently use Bayesian Model Averaging for conditional analysis, a) replicating 88 known associations between HLA alleles and binary disease phenotypes such as cancer, and b) discovering 90 novel associations to phenotypes such as skin and reproductive tract cancers and to other phenotypes not previously associated with the HLA region (e.g. anemias and acne). We find several non-additive effects, suggesting a more complex landscape of disease-modifying effects throughout the region. Finally, we discover associations between homozygous HLA allele burden and several cancer and other phenotypes, suggesting that peptide presentation spectra as coded for by the HLA region are important in determining disease risk. Our results demonstrate the HLA region’s complexity and richness while underscoring its clinical relevance.Competing Interest StatementThe authors have declared no competing interest.