Mendelian randomization uses genetic variants as instrumental variables to estimate the causal effect of a modifiable health exposure or drug target on a downstream outcome. A crucial assumption for accurate estimation of the average causal effect in MR, termed Homogeneity, is that the causal effect does not vary across levels of any instrument used in the analysis. In contrast, the science of pharmacogenetics seeks to actively uncover and exploit genetically driven effect heterogeneity for precision medicine. In this paper we consider a recently proposed method for performing pharmacogenetic analysis on bservational data (The Triangulation WIthin a STudy (TWIST) framework), and explore how it can be combined with traditional MR approaches to properly characterise average and causal effects and genetically driven effect heterogeneity. We propose two new methods which not only estimate the genetically driven effect heterogeneity but also enable the estimation of a causal effect in the genetic group with and without the risk allele separately. Both methods utilise homogeneity-respecting and homogeneity-violating genetic variants and rely on a different set of assumptions. Using data from the ALSPAC study, we apply our new method to estimate the causal effect of smoking before and during pregnancy on offspring birth weight in mothers whose genetics mean they find it (relatively) easier or harder to quit.

The authors have declared no competing interest.

The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and A.J. and J.B. will serve as guarantors for the contents of this paper. Genotyping of the ALSPAC maternal samples were funded by the Wellcome Trust (WT088806). Specific funds for recent detailed data collection on the mothers were obtained from the US National Institutes of Health (R01 DK077659) and Wellcome Trust (WT087997MA) for completion of selected items of obstetric data extraction, including placental weights. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). A.J. received funding for her PhD studentship from the Faculty of Health and Life Sciences at the University of Exeter. J.B. is funded by research grant MR/X011372/1. K.T.A. gratefully acknowledges the financial support of the EPSRC via grant EP/T017856/1. R.F. is supported by a Wellcome Senior Research Fellowship (WT220390). This project utilised high-performance computing funded by the UK Medical Research Council (MRC) Clinical Research Infrastructure Initiative (award number MR/M008924/1). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This research was funded in part, by the Wellcome Trust (Grant number: WT220390). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

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:

Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.

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

The data in ALSPAC is fully available, via managed systems, to any researchers. The managed system is a requirement of the study funders, but access is not restricted on the basis of overlap with other applications to use the data or on the basis of peer review of the proposed science. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. The following steps highlight how to apply for access to the data included in this paper and all other ALSPAC data. (1) Please read the ALSPAC access policy, which describes the process of accessing the data and samples in detail and outlines the costs associated with doing so. (2) You may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011. (3) Please submit your research proposal for consideration by the ALSPAC Executive Committee. You will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please email alspac-data@bristol.ac.uk.