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. 2025 Sep 23;27(10):1684-1694.
doi: 10.1093/ntr/ntaf009.

Genome-Wide Association Study of Varenicline-Aided Smoking Cessation

Kayesha Coley  1 , Qingning Wang  1 , Richard Packer  1   2 , Catherine John  1   2 , Erik Abner  3 , Kadri Reis  3 ; Estonian Biobank Research Team; Khaled F Bedair  4 , Sundararajan Srinivasan  4 , Sara Paciga  5 , Craig Hyde  5 , Robert C Free  2   6 , Nicola F Reeve  1 , David J Shepherd  1 , Tõnu Esko  3   7 , Colin Palmer  4 , Ewan Pearson  4 , Anders Malarstig  8   9 , Martin D Tobin  1   2 , Chiara Batini  1   2
Affiliations

Genome-Wide Association Study of Varenicline-Aided Smoking Cessation

Kayesha Coley et al. Nicotine Tob Res. .

Abstract

Introduction: Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist with the highest therapeutic efficacy of any pharmacological smoking cessation aid and a 12-month cessation rate of 26%. Genetic variation may be associated with varenicline response, but to date, no genome-wide association studies of varenicline response have been published.

Methods: In this study, we investigated the genetic contribution to varenicline effectiveness using two electronic health record-derived phenotypes. We defined short-term varenicline effectiveness (SVE) and long-term varenicline effectiveness (LVE) by assessing smoking status at 3 and 12 months, respectively, after initiating varenicline treatment. In Stage 1, comprising five European cohort studies, we tested genome-wide associations with SVE (1405 cases, 2074 controls) and LVE (1576 cases, 2555 controls), defining sentinel variants (the most strongly associated variant within 1 Mb) with p-value < 5 × 10-6 to follow up in Stage 2. In Stage 2, we tested association between sentinel variants and comparable smoking cessation endpoints in varenicline randomized controlled trials. We subsequently meta-analyzed Stages 1 and 2.

Results: No variants reached genome-wide significance in the meta-analysis. In Stage 1, 10 sentinel variants were associated with SVE and five with LVE at a suggestive significance threshold (p-value < 5 × 10-6); none of these sentinels were previously implicated in varenicline-aided smoking cessation or in genetic studies of smoking behavior.

Conclusions: We provide initial insights into the biological underpinnings of varenicline-aided smoking cessation, through implicating genes involved in various processes, including gene expression, cilium assembly, and early-stage development.

Implications: Leveraging electronic health records, we undertook the largest genetic study of varenicline-aided smoking cessation to date, and the only such study to test genome-wide associations. We showed distinct genetic variants associated (p-value < 5 × 10-6) with varenicline-aided smoking cessation which implicate diverse cellular functions, including transcriptional regulation, RNA modification, and cilium assembly. These provide insights which, if independently corroborated, will improve understanding of varenicline response. The growing availability of biobank resources with genetic and varenicline response data will provide future opportunities for larger studies using the approach we developed.

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Conflict of interest statement

RP and CJ report funding from Orion Pharma outside of the submitted work. MDT has research collaborations with Orion Pharma and GlaxoSmithKline unrelated to the current work. SP, CH, and AM are employees of Pfizer.

Figures

Figure 1.
Figure 1.
Overview of study design. EXCEED = Extended Cohort for E-health, Environment and DNA Study; GoDARTS = Genetics of Diabetes Audit and Research, Tayside and Scotland; GoSHARE = Genetics of the NHS Scotland Health Research Register; MAC = minor allele count; MAF = minor allele frequency.
Figure 2.
Figure 2.
Miami plot for Stage 1 genome-wide association study (GWAS) of short-term varenicline effectiveness (SVE) and long-term varenicline effectiveness (LVE). The gray solid line represents the genome-wide significance threshold (p-value < 5 × 10−8), and the gray dotted line represents the suggestive significance threshold (p-value < 5 × 10−6).
See this image and copyright information in PMC

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