Scientists identified over 500 genetic variants associated with tobacco or alcohol use, in a genome-wide association study recently published in Nature Genetics.
Using a sample of 1.2 million individuals, the investigators linked gene variants to behaviors, including starting smoking at a younger age or consuming more alcoholic drinks per week. Evaluating the physiological effects of these gene variants could help scientists better understand how they contribute to substance misuse disorders, according to Marilyn Cornelis, PhD, assistant professor of Preventive Medicine in the Division of Nutrition and a co-author of the study.
Tobacco and alcohol misuse are significant causes of mortality, and while previous research has suggested those behaviors appear to be heritable, substance misuse has remained resistant to gene discovery, according to the authors.
To overcome this hurdle, investigators obtained individual genetic and self-reported alcohol and smoking behavior data from a variety of databases, including academic institutions around the world, and from commercial genetic testing outlets such as 23andMe. Genome-wide association studies revealed 566 variants associated with behaviors including smoking initiation, cessation and intensity, as well as alcohol use.
Tissue analysis showed these genes were overrepresented — and therefore likely to have biological function — in the hippocampus and prefrontal cortex. According to the study, this is consistent with how alcohol and nicotine use affects neurotransmission in those brain regions, comprising reward-based learning and facilitating drug-seeking behavior.
The investigators also computed risk scores for the National Longitudinal Study of Adolescent to Adult Health (Add Health) and the Health and Retirement Study (HRS) datasets, two cohorts that represent different generations in the United States — Add Health participants were born, on average, in 1979, while average birth year in the HRS was 1938.
These cohorts’ exposure to different tobacco policy environments could have been a confounding factor in this analysis, but despite their very different experiences, subjects in both cohorts had risk scores that were similar: a higher proportion of genes associated with smoking intensity resulted in two more daily cigarettes for the Add Health cohort, and three more daily cigarettes for the HRS cohort.
In addition, the smoking phenotypes correlated with each other, but the alcohol use phenotype only correlated with the smoking initiation phenotype. According to the study, this suggests that the genetic variations affecting alcohol use and beginning to smoke overlap substantially.
Further, variants near a dopamine receptor heavily studied for its involvement in substance misuse disorder were associated with smoking intensity and alcohol use, but not smoking initiation, indicating this receptor is less relevant in early stages of nicotine use.
However, the investigators warn against drawing strong conclusions: substance misuse is a complex disorder with a wide variety of inputs, and these genes are not directly causal. Instead, future studies to tease out what exactly these genes do can help scientists understand how they contribute to substance misuse, according to Cornelis.
“There will be efforts to understand the function or direct relationship between each gene variant and alcohol- or smoking-related traits utilizing various approaches from experimental to clinical, thus involving new investigators with different expertise,” Cornelis said.
This study was supported by funding from US National Institutes of Health awards R01DA037904, R01HG008983 and R21DA040177.
