New Insights on Genetic Risks for Cigarette Smoking

Scientists have long understood that genes play an important role in a person’s smoking behavior, and a new genome-wide association study by Yale and U.S. Department of Veterans Affairs (VA) researchers is helping to explain why some people start to smoke, while others are able to quit.

The study, led by scientists from the Million Veteran Program of the VA and published October 20 in Nature Communications, has linked 99 genetic variants for smoking initiation and 13 variants for smoking cessation among 842,717 people.

Scientists say genetic variants associated with smoking can help them understand why some people are addicted to smoking and others are not. Genetic variants can also explain why some people quit smoking, but others never do.

The VA study validated previously well-established genetic loci for smoking such as CHRNA3, a gene coded acetylcholine receptor subunit A3. More importantly, the study discovered 18 new variants for smoking. Genetic variants close to DRD2 (rs61902812) and on BDNF (rs6265), two of the most-studied genes in psychiatry, are also among significant genes for smoking.

There are over 100 significant loci that are linked to smoking. The investigators prioritized 40 potential causal genes using co-localization analyses that focused on molecular traits such as eQTL and histone interaction in brain tissues.

“This information is important for the next step in studying functional roles of those genes in smoking,” said Ke Xu, MD, Associate Professor of Psychiatry at Yale School of Medicine and co-lead author of the study with Boyang Li, a PhD candidate in the Department of Biostatistics at Yale.

Xu, a staff psychiatrist at the VA Connecticut Healthcare System, said smoking trajectories are highly genetically correlated with other psychiatric disorders and medical conditions. Alcohol use phenotypes, depression, and schizophrenia are positively genetically correlated with smoking behavior.

“These findings may partially explain why cigarette smoking is common among individuals with those psychiatric disorders,” she said.

The study’s senior author, Amy Justice, MD, PhD, CNH Long Professor of Medicine and Public Health at Yale and at VA Connecticut Healthcare System, said, “One of the unique features of this study is its use of smoking trajectories. It leverages the rich longitudinal nature of veterans’ EHR data.”

The study included smoking data recorded in the VA Healthcare System for over 280,000 veterans over 20 years. “The study demonstrates the power of this data for genetic analysis,” Justice said.

Scientists at the University of Pennsylvania collaborated on the study. Other study participants from Yale and the VA include Kathleen McGinnis, DrPH, PhD; Cecilia Dao, PhD; Ning Sun, PhD; Hang Zhou, PhD; William C. Becker, MD; Joel Gelernter, MD; and Hongyu Zhao, PhD.