Genetic and Causal Associations Between Tobacco Smoking and Mental Health After Accounting for General Substance Use and Socioeconomic Factors

Genetic instrumental variable studies can provide stronger insights into the causal relationships between smoking and mental illness than conventional observational studies because they are less susceptible to confounding and reverse causation. However, they still rely on genetic instruments that partly capture genetic influences shared with other substance use and socioeconomic status (SES), potentially biasing estimates of smoking-specific effects. We therefore aim to (1) develop a more specific genetic instrument for smoking that minimizes these shared influences and (2) use this instrument to examine the causal effects of smoking on psychiatric disorders. We applied Genomic Structural Equation Modelling to 19 European-ancestry GWAS summary statistics (7 smoking, 8 substance use and 4 SES phenotypes), deriving a novel smoking-specific genetic factor representing liability to smoking independent of shared substance-use and SES influences. We used this factor as an instrument in Mendelian Randomization analyses to test causal effects of smoking on eight psychiatric disorders. The smoking-specific factor was associated with 52 independent genome-wide significant loci. Genetically predicted smoking-specific liability was significantly causally associated with seven psychiatric disorders. These findings support a causal role of smoking in increasing the risk of multiple psychiatric disorders beyond influences shared with other substance use and SES, providing stronger evidence for smoking-specific effects and informing targeted smoking prevention and intervention strategies. More broadly, our findings highlight that the validity of Mendelian Randomization depends on the specificity of its genetic instruments. Future studies should strive to develop instruments that better isolate the exposure of interest from shared genetic influences, enabling more accurate identification of causal mechanisms.