The UK10K project: rare variants in health and disease. N. Soranzo, The UK10K Consortium Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Understanding of how genetic variation contributes to human traits and which genes are involved is still largely incomplete. Rare and low frequency genetic variants (defined as minor allele frequency [MAF] <1% and 1-5%, respectively) are thought to play a role in common and rare disease, but until recently it has not been possible to assess their contribution systematically. The UK10K project (www.uk10k.org) studies the contribution rare and low frequency variation to a wide spectrum of biomedically relevant quantitative traits and diseases with different predicted genetic architecture. Here we describe the data generated by the different arms of the UK10K project, and use it to address empirically important open questions. We show that the 24 million novel genetic variants identified provide an extensive reference genetic sample for the UK, with fewer than 10% rare variants shared with other large scale resources. The resulting haplotype panel boosts accuracy and coverage of imputation of rare variants in GWAS studies. We discuss the value of these data for discovery and interpretation of variants of clinical importance, including an evaluation of incidental findings that suggests that greater than 5% participants carry rare and potentially actionable genetic variants. We describe how demographic history influences the observed weak structuring of rare variation in the UK (MAF=0.1-0.3%), and evaluate empirically the potential for confounding due to stratification in association studies of complex traits. We describe the contribution of common, low frequency and rare variants to 61 biomedically important quantitative traits, describing novel alleles associated with adiponectin (ADPOQ), lipids (PCSK9, LPL, APOC3|APOA4|APOA1, PCSK7, CETP, LIPG, LDLR and APOE) and several other traits. We further discuss general characteristics of rare variant associations from the comparative evaluation of the allelic architecture of the 61 traits. The data released to the scientific community includes individual-level genotypic and phenotypic data, a reference panel of haplotypes for imputation of rare variants into genome-wide SNP arrays and analysis protocols and summary results for complex trait associations based on single-marker and rare variant aggregation tests. Our results inform future whole-genome and whole-exome sequencing based studies seeking to characterize the role of rare genetic variation in predisposition to rare and common disease.
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