To investigate the pleiotropic mechanisms linking brain structure and function to alcohol drinking and tobacco smoking, we integrated genome-wide data generated by the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN; up to 805,431 participants) with information related to 3,935 brain imaging-derived phenotypes (IDPs) available from UK Biobank (N=33,224). We observed global genetic correlation of smoking behaviors with white matter hyperintensities, the morphology of the superior longitudinal fasciculus, and the mean thickness of pole-occipital. With respect to the latter brain IDP, we identified a local genetic correlation with age at which the individual began smoking regularly (hg38 chr2:35,895,678-36,640,246: rho=1, p=1.01e-5). This region has been previously associated with smoking initiation, educational attainment, chronotype, and cortical thickness. Our genetically informed causal inference analysis using both latent causal variable approach and Mendelian randomization linked the activity of prefrontal and premotor cortex and that of superior and inferior precentral sulci, and cingulate sulci to the number of alcoholic drinks per week (genetic causality proportion, gcp=0.38, p=8.9e-4, rho=-0.18+-0.07; inverse variance weighting, IVW beta=-0.04, 95%CI=-0.07, -0.01). This relationship could be related to the role of these brain regions in the modulation of reward-seeking motivation and the processing of social cues. Overall, 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.

RP received a research grant from Alkermes outside the scope of the present study and is paid for his editorial work on the journal Complex Psychiatry. The other authors declare no competing interests.

Investigators from the University of Camerino acknowledge support from the National Institute of Health/National Institute on Alcohol Abuse and Alcoholism (AA014351 and AA017447) and Ministero dell'Universita' e della Ricerca (PRIN20227HRFPJ). Yale investigators acknowledge support from the National Institutes of Health (R33 DA047527 and RF1 MH132337), One Mind, and the American Foundation for Suicide Prevention (PDF-1-022-21). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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