A novel smoking cessation behavior based on quit attempts may identify new genes associated with long-term abstinence

Smoking cessation at any age has been shown to improve quality of life, decrease illness, and reduce mortality. About half of smokers attempt to quit each year, but only ∼ 7 % maintain long-term abstinence unaided. Few genetic factors have been consistently associated with smoking cessation, possibly due to poor phenotype definition.

We performed a genome-wide association study (GWAS) with an alternative phenotype based on the difficulty of quitting smoking (DQS) in the Cancer Prevention Study-3 cohort. Difficult quitters were defined as having made at least ten quit attempts, whether successful or not, and easy quitters as having quit after only one attempt. Only individuals of European ancestry were selected for the study. Among 10,004 smokers (5,071 difficult quitters, 4,933 easy quitters), we assessed the genetic heritability of DQS and evaluated associations between DQS and each genome-wide variant using logistic regression while adjusting for confounders, including smoking intensity (cigarettes per day).

The genetic heritability of the DQS phenotype was 13 %, comparable to, or higher than, the reported heritability of other smoking behaviors (e.g., smoking intensity, cessation). Although no variants were genome-wide significant, several genes were identified at a subthreshold level (p < 10^-4). A variant in MEGF9 (rs149760032), a transmembrane protein largely expressed in the central nervous system, showed the strongest association with DQS (OR = 0.60, p = 1.3x10^-7). Additional variants associated with DQS independently by smoking intensity were also detected in GLRA3 (rs73006492, OR = 0.77, p = 5.6x10^-7) and FOCAD (rs112251973, OR = 1.96, p = 1.8x10^-6) and are plausibly related to smoking cessation through pathways in the brain and respiratory system.

The use of an alternative cessation phenotype based on difficulty quitting smoking facilitated the identification of new pathways that could lead to unique smoking treatments.