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 (1,405 cases, 2,074 controls) and LVE (1,576 cases, 2,555 controls), defining sentinel variants (the most strongly associated variant within 1 megabase) 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 randomised controlled trials. We subsequently meta-analysed 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 behaviour. 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.

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.

This study was supported by specific personal funding from the following: Wellcome Trust Investigator Award (WT202849/Z/16/Z), Wellcome Trust Discovery Award (WT225221/Z/22/Z), MRC grant number MR/N011317/1 and NIHR Senior Investigator Award to MDT; and UKRI Innovation Fellowship at Health Data Research UK grant number MR/S003762/1 to CB. This research is funded by the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UK Biobank genetic and phenotypic data were obtained under UK Biobank Applications 4982 and 59822. UK Biobank has ethical approval from the UK National Health Service (NHS) National Research Ethics Service (11/NW/0382). EXCEED received ethical approval from the Leicester Central Research Ethics Committee (13/EM/0226), and substantial amendments have been approved by the same Research Ethics Committee for the collection of new data relating to the COVID-19 pandemic, including the COVID-19 questionnaires and antibody testing. Individual level data analysis in Estonian Biobank was carried out under ethical approval 1.1-12/624 from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs), using data according to release application 6-7/GI/33501 from the Estonian Biobank. . GoDARTS and SHARE studies were reviewed and approved by Tayside Medical Ethics Committee 053/04 and East of Scotland Ethics Committee NHS REC 13/ES/0020.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Summary statistics from SVE and LVE Stage 1 meta-analyses are being deposited at the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas/) and accession numbers will be added as soon as they are available.