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Beyond the Genetics of Addiction

Final Report Summary - ADDICTION (Beyond the Genetics of Addiction)

Substance use (nicotine, alcohol, cannabis, caffeine) is common, and use or abuse of substances have well-known negative health consequences, although there are exceptions because small amounts of caffeine and alcohol are not associated with adverse health effects. There are large individual differences in substance use, abuse and addiction. Some people become highly addicted while others can easily quit their substance use. Both heritable and environmental factors play a role in substance use and in order to understand the cause of the individual differences we need to unravel these heritable factors and their interplay with the environment.

In our project we showed that (at least partly) the same genetic factors are associated with different substances. For example, we showed that the genetic factors influencing caffeine consumption and smoking overlap, but also genetic factors influencing (poly) substance use and sugar intake through drinks (based on twin-studies). These results suggest an underlying genetic vulnerability for substance use or addictive behavior in general. In line with this, we showed high genetic correlations between smoking, alcohol, cannabis, caffeine using the results of genome-wide association studies (DNA studies). Moreover, we observed stage-specific genetic effects across substances: a high genetic correlations was observed for initiation of substance use (smoking, cannabis) and between quantity of substance use (cigarettes per day, alcohol per week and coffee per day).

To find specific genes for complex behavior such as substance use it is essential to collaborate in large consortia. We participated in several large existing gene-finding consortia for substance use (smoking, alcohol) but in addition we established the International Cannabis Consortium (ICC) ourselves. We performed the largest GWA meta analyses for lifetime cannabis to date (N~35,000, 16 research groups) and we have found 4 genes involved in cannabis use, including NCAM1 (previously associated with other substance use) and CADM2 (recently associated with personality and risk taking behavior).

From twin studies it is known that both genetic factors and environmental factors contribute to individual differences in substance use, and possibly these factors also interact with each other (GxE). We found mixed evidence for GxE interactions in substance use. We did find a GxE interaction for genetic vulnerability for smoking and exposure to smoking during childhood on heavy smoking in adulthood, but no interaction between a genetic vulnerability for smoking and having a smoking spouse on smoking during pregnancy. We also did not find an interaction between genetic vulnerability for alcohol use and experiencing stress or low satisfaction with life on alcohol use or abuse.

With regard to the consequences of smoking behavior we showed that smokers have differential gene-expression patterns compared to non-smokers. For most genes this pattern is reversible after smoking cessation so these gene expression differences seem to be direct consequences of smoking. We also showed (with a discordant twin design) that smoking in adolescence can cause an increase in attention problem scores, lasting into adulthood.

In summary, this project facilitated to do research to the role of genetic factors and the interaction with environment in substance use and abuse on different levels and with different approaches, which has led to novel scientific knowledge in the field of addictive behavior.