Leveraging Genomic Data to Examine the Causal Impact of Alcohol, Tobacco, Cannabis, and Opioid Use on Biological and Cognitive Ageing.

Although substance use is associated with a shortened lifespan, impeded health and accelerated biological ageing, the factors contributing to the associations between substance use and ageing are poorly understood. We used summary statistics from genome-wide association studies (GWAS) to investigate whether substance involvement (N from 28K to 2M)-including alcohol, tobacco, cannabis and opioid use and use disorders-is genetically correlated with various ageing metrics (N from 162K to 2.7M) and whether these correlations reflect shared genetic etiologies or putative causal relationships. Using Linkage Disequilibrium Score Regression (LDSC), we found widespread evidence of genetic correlations between substance use/use disorders and indices of physical, cognitive and biological ageing. We then employed a series of Mendelian randomization-based approaches, finding significant causal effects of genetic predispositions to both tobacco use disorder and quantity of tobacco smoked on various markers of ageing. Causal effects of problematic alcohol use and cannabis use disorder were also found, though findings were mixed. Evidence of reverse causality (i.e., ageing causing substance use), meanwhile, was scant. Collectively, these results demonstrate strong triangulation across approaches and highlight the importance of integrating genetic insights into public health strategies for reducing the burden of SUDs across the lifespan.