Noncoding rare variant associations with blood traits in 166,740 UK Biobank genomes

Abstract

Large biobanks with whole-genome sequencing (WGS) now enable the association of noncoding rare variants with complex human traits. Given that >98% of the genome is available for exploration, the selection of noncoding variants remains a critical yet unresolved challenge in these analyses. Here we leverage knowledge of blood gene regulation and deleteriousness scores to select noncoding variants pertinent for association with blood-related traits. Integrating WGS and 42 blood cell count and biomarker measurements for 166,740 UK Biobank samples, we perform variant collapsing tests, identifying hundreds of gene–trait associations involving noncoding variants. However, we demonstrate that most of these noncoding rare variant associations (1) reproduce associations known from previous studies and (2) are driven by linkage disequilibrium between nearby common and rare variants. This study underscores the prevailing challenges in rare variant analysis and the need for caution when interpreting noncoding rare variant association results. Noncoding rare variant analyses using whole-genome sequencing data from the UK Biobank identify gene–trait associations for 42 blood cell traits but find that most signals are driven by linkage disequilibrium between common and rare variants.