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

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...

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Vydáno v:Nature genetics Ročník 57; číslo 9; s. 2146
Hlavní autoři: Ribeiro, Diogo M, Hofmeister, Robin J, Rubinacci, Simone, Delaneau, Olivier
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.09.2025
Témata:
Biological Specimen Banks
Genetic Variation
Genome, Human - genetics
Genome-Wide Association Study
Humans
Linkage Disequilibrium - genetics
Polymorphism, Single Nucleotide - genetics
Quantitative Trait Loci
UK Biobank
United Kingdom
Whole Genome Sequencing
United Kingdom
ISSN:1546-1718, 1546-1718
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
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ISSN:1546-1718
1546-1718
DOI:10.1038/s41588-025-02288-x