Genome-wide association studies of substance-use disorders, including problematic tobacco, alcohol, cannabis and opioid use, have provided evidence for a component of genetic liability that is shared across these traits. To explore this shared liability, Hatoum et al. performed multivariate genome-wide association analyses combining datasets for problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a total sample size of over 1 million individuals. They found that a general addiction risk factor, defined using genomic structural equation modeling, was associated with 17 independent loci at genome-wide significance. Gene-based analyses further identified associations with 42 genes, including FTO, DRD2 and PDE4B, while linkage disequilibrium score regression analyses identified positive genetic correlations with several traits, including suicide attempt, self-medication for anxiety or depression, and externalizing behaviors. In a follow-up study of 4,491 substance-naive children, a polygenic score for the general addiction risk factor was positively correlated with several traits, including childhood externalizing behaviors, thought problems, sleep duration, and family history of substance abuse and mental illness. These analyses provide clues into the biological pathways that influence substance-use disorders and their relationship with other behavioral traits.
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