Finding genome-transcriptome-phenome association with structured association mapping and visualization in genamap

Despite the success of genome-wide association studies in detecting novel disease variants, we are still far from a complete understanding of the mechanisms through which variants cause disease. Most of previous studies have considered only genome-phenome associations. However, the integration of transcriptome data may help further elucidate the mechanisms through which genetic mutations lead to disease and uncover potential pathways to target for treatment. We present a novel structured association mapping strategy for finding genome-transcriptome-phenome associations when SNP, gene-expression, and phenotype data are available for the same cohort. We do so via a two-step procedure where genome-transcriptome associations are identified by GFlasso, a sparse regression technique presented previously. Transcriptome-phenome associations are then found by a novel proposed method called gGFlasso, which leverages structure inherent in the genes and phenotypic traits. Due to the complex nature of three-way association results, visualization tools can aid in the discovery of causal SNPs and regulatory mechanisms affecting diseases. Using wellgrounded visualization techniques, we have designed new visualizations that filter through large three-way association results to detect interesting SNPs and associated genes and traits. The two-step GFlasso-gGFlasso algorithmic approach and new visualizations are integrated into GenAMap, a visual analytics system for structured association mapping. Results on simulated datasets show that our approach has the potential to increase the sensitivity and specificity of association studies, compared to existing procedures that do not exploit the full structural information of the data. We report results from an analysis on a publically available mouse dataset, showing that identified SNP-gene-trait associations are compatible with known biology.