Integrative multi-ethnic Mendelian randomisation identifies tissue-specific causal genes for Coronary Artery Disease and interactions with post-acute Covid

Coronary artery disease (CAD) is highly heritable and remains the leading cause of mortality worldwide. Understanding the genetic and mechanistic underpinnings of CAD is crucial for early risk assessment and intervention. We conducted a transcriptome-wide Mendelian randomisation (MR) study, utilising unbiased tissue-specific gene regulatory networks, to identify genes causally associated with CAD in European and East Asian populations. We identified 291 tissue and ancestry-specific genes implicated in CAD, including 98 novel protein-coding genes across coronary artery, whole blood, and lung tissues. Genes involved in epigenetic processes (eg PAXBP and KIAA0232 ) causally associated with CAD. Moreover, we identified genes related to the ubiquitin-proteasome system in the coronary artery and kinase signalling in the lung, as being causally related to CAD. The integration of protein interaction networks identified causal connections between CAD and HDL cholesterol levels, providing novel insights into CAD mechanisms, and potential actionable targets for people with this risk profile. The results also provide intriguing insights into the link between SARS-CoV-2 and CAD, unveiling mechanisms that may underlie the increased risk of cardiovascular disease following SARS-CoV-2 infection. The causal mechanisms we identified emphasise the tissue-agnostic and ancestrally unique pathways that underscore the complex interplay between CAD development, metabolic disturbances, and the immune system. Collectively, our results provide valuable insights into CAD pathogenesis and potential therapeutic targets.