Anasthasia Shilov, Illustrations Editor

A new Yale study reveals genetic markers that may predict which people are more likely to start and stop smoking than others.

The study was published in the journal Nature on Oct. 20, co-authored by professor of psychiatry at the Yale School of Medicine Ke Xu and biostatistics doctoral candidate Boyang Li GRD ’23. Through a genome-wide association study, or GWAS, the researchers identified 99 genetic variants linked to smoking initiation and 13 variants linked to smoking cessation. This research was funded by the U.S. Department of Veterans Affairs and was part of its Million Veteran Program.

“In the future,” Xu said, “our goal is to use this as information to identify some provisional strategies to help veterans and also the general population … [quit] smoking.”

According to the VA website, over 825,000 veterans have partnered with the Million Veteran Program since its launch in 2011. Xu and Li’s research was directly tied to the program’s aim to understand how genetic and environmental factors affect the health outcomes of individuals. 

The researchers’ work used data from veterans provided by the Million Veteran Program and specifically compared the genomes of these individuals. One benefit of accessing this data was the varying populations which they were able to study.

“We are not looking at the widely studied European population,” Xu said. “We also look at other populations including African Americans and Hispanic Americans.”

With this large, ethnically diverse cohort they were able to access longitudinal data — which is data collected over an extended period of time — about the smoking history of the patients. They then identified particular loci, or locations, of genetic variations which may be linked to a patient’s likelihood of smoking.

Once researchers identify certain genetic markers that increase an individual’s likelihood of smoking, it becomes possible to treat people with these risk factors in a more targeted way.

“If we can use genetics to construct a sort of vulnerability or liability of certain complex traits,” Li said. “We can then help them to actually change their behavior … for a better health outcome.”

While the study focuses on the way a person’s genetics affect their smoking behavior, Xu specified that genes are not the only determining factor behind why a person may be more or less likely to smoke. She mentioned that the estimated heritability of smoking is about 40 to 50 percent, meaning that other environmental factors have a role to play.

According to Xu, education and policy can be important variables. Some examples of previously studied environmental variables include taxes on tobacco sales, smoke-free regulations and limits on sales and marketing of tobacco products. All of these have been proven to reduce tobacco use, according to a 2014 study.

While a person’s genetics may not be the whole picture, they are an immutable contributor to smoking risk, according to Li. Xu said that the next step is to use genetic variants to investigate the relationship between substance abuse and psychiatric disorders.

Antonio Giraldez, chair of the Department of Genetics, believes this study is a step forward in learning about the basic biology that guides individuals’ decision making with regards to addiction.

“Understanding that certain genes, when they have a particular mutation, give a preference for smoking versus not smoking is … a window into understanding the neurological pathways that guide decision-making,” he said.

According to Giraldez, however, the genetic variations the study identified are only loosely linked to particular genes, and some may affect multiple genes simultaneously. He mentioned that scientists’ understanding of which genes affect smoking initiation or cessation is thus uncertain, and there is a lot more work to be done before the research can be used in clinical practice.

The next step in this research, Giraldez said, is to replicate the study with another large cohort. According to the paper, the researchers were unable to replicate their findings as part of their paper.

“The reason for that is not necessarily that the findings were not true,” Giraldez said. “It’s that they couldn’t reach statistical significance based on the statistical power of their study.”

Essentially, they were unable to find a suitably large cohort with which to replicate their data. Nevertheless, this study has shed light on how genetics can impact one’s smoking behavior, which may eventually be used to produce targeted treatments.

Smoking is responsible for more than 480,000 deaths per year in the United States and remains the largest preventable cause of death in the country.

Amre Proman | amre.proman@yale.edu

Kaitlin Flores | kaitlin.flores@yale.edu