In this Review, we focus on the largest and the most consequential studies based on genome-wide designs (Figure 1; Table 1). We discuss legal and illegal substances separately. Why so? This is not simply an administrative, or legal, issue. The environmental effects of exposure to various substances play a critical role in determining how an individual’s genetic risk to become addicted [G] plays out; and legality plays a large role in exposure. Also, societies have tended to legalize those substances that are considered to be less harmful (at least at the time they are legalized) or to which exposure is deemed inevitable and impossible to control. The unequivocally illegal substances, for example cocaine and opioids, are considered very harmful, and their use has comparatively low prevalence; the unequivocally legal ones, especially alcohol and tobacco, are freely available to almost everyone and are used more widely. Cannabis straddles the two categories. We describe emerging biological insights, including from large-effect loci, and genetic overlap among SUDs and related traits. We also discuss how genomics studies can be complemented by other omics approaches
