Deciphering Genetic Traits Toward Alcohol Drinking

Considering the intricate nature of alcohol consumption behaviors and their varied manifestations, this thesis aims to unveil novel insight and perspectives on causal mechanism aƯecting patterns within alcohol consumption and their interplay with other related traits. In the first chapter of this thesis, we focus our attentions upon the consistent pattern of low alcohol consumptions among of Asian populations (Manthey et al., 2019). Carriers of ADH1B2 (Arg48His, rs1229984) and ALDH22 (Glu504Lys, rs671) genetic variants are recognized for their heightened sensitivity to the adverse eƯects of alcohol consumption due to their eƯect on acetaldehyde toxicity. Notably, these two functional genetic variations are mostly prevalent within the Southeast Asia Region (SAER) and are rarely found in non-Asian populations (Polimanti & Gelernter, 2018; Zhang et al., 2021). While the magnitude of selective pressure exerted on population living in SAER is well known; postulated the content of “the aldehyde hypothesis” (Darwin & Stanley, 2022), ours was the first study to systematically evaluate the contribution of infectious diseases and other ecological variables to the selection these two genomic variants in Asian populations (Deiana et al., 2024). Our analyses suggest that Mycobacteria may have played a role in the joint selection of ADH1B*2 and ALDH2*2. Later in the second chapter, we conducted an extensive review of available data on RNA-seq data for AUD and PTSD to find signals of shared transcriptomic signatures between the two. our analysis evaluated for the first time the explanatory role of shared enriched pathways across dorsolateral prefrontal cortex and basolateral amygdala on bidirectional pattern of comorbidity linking AUD and PTSD (Dell'Aquila & Berle, 2023). Our results underline the role of family A (rhodopsin-like) G-protein coupled receptors (GPCRs), and tyrosine kinases receptors (RTKs), and their clinical aƯordance in both AUD and PTSD. Lastly, in the third chapter, we investigated the pleiotropic mechanisms linking brain structure and function to alcohol and tobacco use. Given the complex interplay of alcohol and nicotine with human brain (Alcohol & Drug Use, 2018; He et al., 2022), we applied a wide apparatus of post GWAS analysis including linkage disequilibrium score regression (Bulik-Sullivan et al., 2015), local analysis of [co]variant association (Werme et al., 2022) and genetically inferred causal inference analyses (Hemani et al., 2018; O'Connor & Price, 2018). Our brain-wide investigation highlighted that different pleiotropic mechanisms likely contribute to the relationship of brain structure and function with alcohol drinking and tobacco smoking, suggesting decision-making activities and chemosensory processing as modulators of propensity towards alcohol and tobacco consumption.