Understanding the genetic risk and mechanisms through which SARS-CoV-2 infection outcomes and comorbidities interact to impact acute and long-term sequelae is essential if we are to reduce the ongoing health burdens of the COVID-19 pandemic. Here we use a de novo protein diffusion network analysis coupled with tissue-specific gene regulatory networks, to examine putative mechanisms for associations between SARS-CoV-2 infection outcomes and comorbidities. Our approach identifies a shared genetic aetiology and molecular mechanisms for known and previously unknown comorbidities of SARS-CoV-2 infection outcomes. Additionally, genomic variants, genes and biological pathways that provide putative causal mechanisms connecting inherited risk factors for SARS-CoV-2 infection and coronary artery disease and Parkinson’s disease are identified for the first time. Our findings provide an in depth understanding of genetic impacts on traits that collectively alter an individual’s predisposition to acute and post-acute SARS-CoV-2 infection outcomes. The existence of complex inter-relationships between the comorbidities we identify raises the possibility of a much greater post-acute burden arising from SARS-CoV-2 infection if this genetic predisposition is realised.