Your Illness on Drugs: the Genetics of Substance Use Informs Our Response to Somatic Diseases

Edenberg, H.; Hatoum, A.; Agrawal, A.

Overall Abstract: SUDs are among the top contributors to all cause mortality. This session highlights cross-cutting genetic and genomic analyses that illuminate the relationships between substance use disorders (SUDs) and aspects of health and disease beyond the known relationships with other psychiatric disorders. This is a topic that has gotten very little attention in the past. It is timely, given multiple global health crises, as it addresses the role of SUDs in respiratory and cardiometabolic illness, COVID-19 and HIV/AIDS – each among the leading contributors to mortality. The first talk will showcase findings from a phenome-wide analysis (PheWAS) of alcohol and cannabis involvement, using medical center data. It demonstrates that genetic liability for substance use has a profound effect on multiple bodily systems. For example, genetic liability for cannabis use predicted respiratory illness while that for alcohol use predicted heart disease. Individuals with SUDs are at higher risk to develop severe cases of COVID-19. The second talk examines genetic correlations between COVID-19 severity phenotypes and 1014 heritable traits, and reveals that the largest genetic causality proportions were for alcohol use frequency, smoking and cannabis use. Third, we pivot from the current pandemic to the ongoing HIV epidemic to discuss the impact of cocaine abuse among HIV+ individuals. The findings showed cocaine use increased viral load, worsened progression, accelerated mortality, and increase the latent viral reservoir. Specific DNA methylation and gene expression differences that appear to be biological mediators of these relationships were uncovered. The last talk addresses the mediating role of behavioral disinhibition, which is genetically correlated with SUD, using a multivariate GWAS approach to creating a broad genetic measure of externalizing behavior (EXT). Pooling data from ∼1.5 million people, more than 500 genetic loci were discovered. A PheWAS showed that EXT-PRS was associated with 255 of the 1335 disease phenotypes tested (FDR < 0.05). Individuals with higher EXT-PRS showed poorer health in nearly every bodily system. To conclude, the panel will discuss the importance of considering the genetics of SUDs more broadly, to better understand both psychiatric and somatic disorders and the enormous health burden arising from them. Disclosure: Nothing to disclose.