Pervasive additive and non-additive effects within the HLA region contribute to disease risk in the UK Biobank

Abstract

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.

Significant Sparse Polygenic Risk Scores across 813 traits in UK Biobank

“…For celiac disease, an autoimmune disorder that affects the small intestine from gluten consumption, for example, the sparse PRS model consists of 428 variants that contain the imputed HLA allelotypes and variants near the MHC region in chromosome 6 [16,18]. The PRS model also contains genetic variants in all other autosomes, including a previously implicated missense variant in the chromosome 12 (rs3184504, log(OR) = 0.15 in multivariate PRS model) in SH2B3 that encodes SH2B adaptor protein 3 involving in cellular signaling, hematopoiesis, and cytokine receptors [21] (Fig.…”

Using de novo assembly to identify structural variation of eight complex immune system gene regions

“…Variation in genes encoding some of these components have wellestablished associations with infectious, immune-mediated, and other disease traits. The major histocompatibility complex (MHC) encoding HLA is so far the best-studied example, with hundreds of associations now known across multiple classes of disease [1,2] including infections [3,4]. In some cases the underlying functional mechanisms have also been identified [5,6].…”

Fast Numerical Optimization for Genome Sequencing Data in Population Biobanks

“…CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted February 16, 2021. ; https://doi.org/10.1101/2021.02.14.431030 doi: bioRxiv preprint genotyped variants (release version 2 of Sudlow et al (2015)), the imputed allelotypes in human leukocyte antigen allelotypes (Venkataraman et al 2020), and copy number variations described in Aguirre et al (2019), resulting in a genotype matrix of 1, 080, 968 variants, as described in Sinnott-Armstrong et al (2021). The study population consists of 337, 129 unrelated participants of white British ancestry described in DeBoever et al 2018.…”

“…The vertical axis is the ratio of between time spent in the baseline and the time spent with the compact representation. The baseline for Xβ is 9.8 seconds.genotyped variants (release version 2 ofSudlow et al (2015)), the imputed allelotypes in human leukocyte antigen allelotypes(Venkataraman et al 2020), and copy number variations described inAguirre et al (2019), resulting in a genotype matrix of 1, 080, 968 variants, as described inSinnott- Armstrong et al (2021). The study population consists of 337, 129 unrelated participants of white British ancestry described inDeBoever et al (2018).…”