The consistent genetic correlation among SUDs and other psychiatric disorders could be due to shared genetic effects or causal effects between the traits98. Mendelian randomization (MR) methods leverage instrumental variables based on genetic information to distinguish simple association from causation99. Alcohol drinking and tobacco smoking behaviours have been investigated using known risk alleles in the ALDH2, ADH1B and CHRNA5–CHRNA3–CHRNB4 loci to test causal relationships with respect to mental and physical health100–108. MR approaches based on polygenic instrumental variables are more powerful, and allow for exploration of a wider range of hypotheses, including testing the difference between phenotypes based on diagnostic criteria and those based on consumption and frequency use82. Two-sample MR approaches, which are based exclusively on genome-wide association statistics, reduced the limitations due to the use of individual-level data, allowing for a more extensive range of studies109. Polygenic instruments were investigated to test the causal links between traits related to tobacco smoking with psychiatric disorders and behavioural traits. Smoking initiation is affected by educational attainment but not by cognitive ability, suggesting a contribution to health inequality in less-educated people110.
