Abstract
We conducted the first comprehensive association analysis of a coronary artery disease (CAD) cohort within the recently released UK Biobank (UKB) whole genome sequencing dataset. We employed fine mapping tool PolyFun and pinpoint rs10757274 as the most likely causal SNV within the 9p21.3 CAD risk locus. Notably, we show that machine-learning (ML) approaches, REGENIE and VariantSpark, exhibited greater sensitivity compared to traditional single-SNV logistic regression, uncovering rs28451064 a known risk locus in 21q22.11. Our findings underscore the utility of leveraging advanced computational techniques and cloud-based resources for mega-biobank analyses. Aligning with the paradigm shift of bringing compute to data, we demonstrate a 44% cost reduction and 94% speedup through compute architecture optimisation on UK Biobank's Research Analysis Platform using our RAPpoet approach. We discuss three considerations for researchers implementing novel workflows for datasets hosted on cloud-platforms, to pave the way for harnessing mega-biobank-sized data through scalable, cost-effective cloud computing solutions.