How DNA Influences How Much You’ll Smoke

A new study from the University of Colorado Boulder has shed light on how genetic variations influence smoking behaviors, providing valuable insights into the complex interplay between genes and nicotine addiction.

The research, published in the journal Drug and Alcohol Dependence, focuses on the most well-known smoking-related genetic variant, nicknamed “Mr. Big,” and how it interacts with other genetic differences to shape an individual’s smoking habits.

Pamela Romero Villela, a PhD student in the Department of Psychology and Neuroscience and the study’s first author, emphasizes the importance of understanding the genetic factors behind smoking. “We know that smoking is highly heritable, with genetic differences accounting for 40% to 75% of the differences in people’s smoking behaviors,” she said. “The more we can understand what those genes do and how they interact, the better equipped we will be to develop personalized approaches to helping people quit.”

The study zeroed in on the single nucleotide polymorphism (SNP) rs16969968, known as “Mr. Big,” which is located in a gene called CHRNA5F (nicotinic acetylcholine receptor 5) and influences how well nicotine binds to receptors in the brain. People with a certain version of Mr. Big, known as the AA version, are less sensitive to nicotine and have been shown to smoke more.

“It kind of numbs your response so in order for you to feel the same effect as someone who smoked one cigarette you might have to smoke almost one and a half cigarettes,” Romero Villela explained.

However, the study reveals that the story does not end there. When analyzing genetic information from about 165,000 current or former smokers of European, South Asian, and Finnish descent, the team discovered genes and variants in a completely different region of the genome that appear to interact with Mr. Big in a way that influences smoking habits.

Notably, when people had the risk-boosting version of Mr. Big but also had a genetic variant called rs73586411, they smoked significantly less than expected. “We basically found another variant that ameliorates the effect of Mr. Big,” said Romero Villela.

The study’s authors envision a future where people could be given a “polygenic risk score” that considers their gene variants and interactions to provide personalized recommendations for quitting. Preliminary studies have already suggested that people with high-risk genotypes in the CHRNA5 region may benefit more from medications targeting nicotinic receptors.

Marissa Ehringer, a professor of Integrative Physiology who has studied substance use disorders for more than 20 years and collaborated with Romero Villela on the study, emphasizes the importance of understanding genetic interactions. “Genes don’t operate in a vacuum,” she said. “If our ultimate goal is more personalized medicine, we have to understand these interactions better.”

More research is needed to fully understand the functions of the genes highlighted in the study. One gene called TMEM230, for example, has previously been associated with Parkinson’s disease, and nicotine is known to blunt some symptoms of the disease.

Eventually, if researchers could determine what a variant does to dull the craving to smoke, they might be able to develop medications that mimic that action. The study’s authors hope that their findings will inspire more research looking not just at individual genes but also at how genetic variants work together.

With smoking linked to one in five deaths in the United States and nicotine being one of the hardest drugs to quit, understanding the genetic factors behind smoking is crucial. By unraveling the complex genetic puzzle of nicotine addiction, researchers can work towards developing more effective, personalized approaches to help people quit smoking and improve public health.