Uncovering hidden gene-trait patterns through biclustering analysis of the UK Biobank

The growing availability of genome-wide association studies (GWAS) and large-scale biobanks provides an unprecedented opportunity to explore the genetic basis of complex traits and diseases. However, with this vast amount of data comes the challenge of interpreting numerous associations across thousands of traits, especially given the high polygenicity and pleiotropy underlying complex phenotypes. Traditional clustering methods, which identify global patterns in data, lack the resolution to capture overlapping associations relevant to subsets of traits or genes. Consequently, there is a critical need for innovative analytic approaches capable of revealing local, biologically meaningful patterns that could advance our understanding of trait comorbidities and gene-trait interactions. Here, we applied BiBit, a biclustering algorithm, to transcriptome-wide association study (TWAS) results from PhenomeXcan, a large resource of gene-trait associations derived from the UK Biobank. BiBit allows simultaneous grouping of traits and genes, identifying biclusters that represent local, overlapping associations. Our analyses uncovered biologically interpretable patterns, including asthma-related biclusters enriched for immune-related gene sets, connections between eye traits and blood pressure, and associations between dietary traits, high cholesterol, and specific loci on chromosome 19. These biclusters highlight gene-trait relationships and patterns of trait co-occurrence that may otherwise be obscured by traditional methods. Our findings demonstrate that biclustering can provide a nuanced view of the genetic architecture of complex traits, offering insights into pleiotropy and disease mechanisms. By enabling the exploration of complex, overlapping patterns within biobank-scale datasets, this approach provides a valuable framework for advancing research on genetic associations, comorbidities, and polygenic traits.