Clinical laboratory tests are a critical component of the continuum of care and provide a means for rapid diagnosis and monitoring of chronic disease. In this study, we systematically evaluated the genetic basis of 38 blood and urine laboratory tests measured in 358,072 participants in the UK Biobank and identified 1,857 independent loci associated with at least one laboratory test, including 488 largeeffect protein truncating, missense, and copynumber variants. We tested these loci for enrichment in specific single cell types in kidney, liver, and pancreas relevant to disease aetiology. We then causally linked the biomarkers to medically relevant phenotypes through genetic correlation and Mendelian randomization. Finally, we developed polygenic risk scores (PRS) for each biomarker and built multiPRS models using all 38 PRSs simultaneously. We found substantially improved prediction of incidence in FinnGen (n=135,500) with the multiPRS relative to singledisease PRSs for renal failure, myocardial infarction, liver fat percentage, and alcoholic cirrhosis. Together, our results show the genetic basis of these biomarkers, which tissues contribute to the biomarker function, the causal influences of the biomarkers, and how we can use this to predict disease. 45 50 55 60 65 70 75 80 85 90 95 100
Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β =-0.53 and-0.67 mmHg for heterozygotes,-3.40 and-2.37 mmHg for homozygotes, P = 5.96 x 10 −9 and 1.07 x 10 −13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10 −12 for all glaucoma types and also protection against its subtypes including exfoliation, primary openangle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.
We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. We report 813 sparse PRS models with significant (p < 2.5 x 10−5) incremental predictive performance when compared against the covariate-only model that considers age, sex, types of genotyping arrays, and the principal component loadings of genotypes. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance (Spearman’s ⍴ = 0.61, p = 2.2 x 10−59 for quantitative traits, ⍴ = 0.21, p = 9.6 x 10−4 for binary traits). The sparse PRS model trained on European individuals showed limited transferability when evaluated on non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).
We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,600 traits using genetic and phenotype data in the UK Biobank. We report 428 sparse PRS models with significant (p < 2.5e-5) incremental predictive performance when compared against the covariate-only model that considers age, sex, and the genotype principal components. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance in quantitative traits (Spearman's ρ = 0.54, p = 1.4e-15), but not in binary traits (ρ = 0.059, p = 0.35). The sparse PRS model trained on European individuals showed limited transferability when evaluated on individuals from non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).
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.
Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD); however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequence data from more than 30,000 CD cases and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.
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