Genetic causes of addictions are revealed

Substance use disorders cause enormous damage to both individuals and society as a whole. Twin studies have long indicated a significant genetic contribution to the development of addictions: up to 80% of the genetic influences associated with alcohol addiction are shared with other disorders in this spectrum, while for other addictions, this share reaches 74%. The remaining genetic component is specific to the substance in question and cannot be attributed to non-genetic risk factors.

Addictions are part of the so-called externalizing spectrum, which includes disorders and behaviors based on behavioral hyperactivity: childhood behavioral disorders, antisocial behavior in adults, and a tendency to break rules. The genetic foundation of this spectrum is estimated to be inherited by up to 80%, which is significantly higher than the heritability of any individual disorder. However, most genomic studies have focused on identifying risk genes for each specific addiction individually.

The authors of the new study asked whether the genes associated with externalizing behavior differ from the genes that increase the risk of addiction, or whether they are the same set. To answer this question, they built two competing genomic models and tested them on data from more than 2.2 million participants with 5.9 million genetic variants. The first model considered addiction as part of a single externalizing factor. The second model divided behavioral hyperactivity and addiction into two separate but closely correlated factors.

The first model identified 708 genetic loci, of which 26% were associated with externalizing traits or addiction for the first time, and 57% were associated with substance use-related traits for the first time. The second model identified 631 loci for the hyperactivity factor and 48 loci for the addiction factor. Models that focused solely on addiction and did not consider externalizing traits did not identify any new genetic signals, highlighting the value of an integrated approach.

Among the genes specific to particular addictions, those that code for the enzymes of the metabolism of the respective substances were found. This means that the genetically encoded sensitivity to alcohol or nicotine, which determines how quickly and by what route the body processes these substances, itself affects the likelihood of addiction. Polygenic risk scales calculated for these specific genes better predicted a particular type of addiction, while a broader scale based on an externalizing factor reflected a general predisposition to addictive behavior.

The practical perspective of this division is that a doctor, when evaluating a patient, can take into account both the broad profile of externalizing risk and the specific vulnerability to a particular substance. Additionally, the authors have identified over 100 target genes that could be repurposed for existing drugs, particularly those approved for drug-assisted addiction treatment, although they acknowledge that these candidates still require clinical validation.

The researchers also noted that some of the residual genetic risk of addiction operates through mechanisms unrelated to the externalizing spectrum and may overlap with internalizing disorders and thought disorders. This highlights the need for comprehensive psychiatric assessment of patients with addiction.

The limitations of the study primarily relate to the sample size, as all participants were of European descent. In addition, the analysis of residual risk depends on the statistical power of the original genome-wide studies, and non-externalizing forms of mental disorders associated with addictions were not taken into account in the models.