Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual's genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. Pharmacogenetic information is most often obtained using special assays, making it expensive and time-consuming to generate. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing, and lowering the barrier to generating PGx information prior to first prescription. Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a novel CYP2D6 copy number variant calling tool, foregoing the need to use separate PCR-based copy number detection. Ultimately, we returned 1227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.

NdBV and DTo are members of the Dutch Pharmacogenetics Working Group (DPWG). All other authors report no conflict of interest.

This work was supported by SNN (Samenwerkingsverband Noord Nederland) [OPSNN0229 PCH Ecosysteem WP4.4 ]; by Lifelines NEXT, which has been made possible by funds from a grant from the UMCG Hereditary Metabolic Diseases Fund; by the grants awarded to A.Z. (Netherlands Organization for Scientific Research [NWO] VIDI Grant [016.178.056], a European Research Council [ERC] starting grant [ERC-715772], and Gravitation program EXPOSOME-NL (NWO grant number 024.004.017)), and the Lifelines Biobank initiative, which has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN and REP (Ruimtelijk Economisch Programma). L.F. is supported by grants from NWO [ZonMW-VIDI 917.14.374, ZonMW-VICI 09150182010019], by an ERC Starting grant [637640 ImmRisk] and through a Senior Investigator grant from the Oncode Institute. P.D. is funded by The Netherlands Organisation for Health Research and Development (ZonMw) [VENI 09150161910057].

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

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

The Medical Ethics Review Board of University Medical Center Groningen gave ethical approval for this work.

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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).

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

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Due to privacy reasons the individual-level data cannot be made publicly available but can be made available upon reasonable request. The individual-level data from Lifelines that support the findings in this publication were obtained from the Lifelines biobank under project application number ov21_0355. This request should be directed to the Lifelines Research Office through email (research@lifelines.nl) or by using the application form on their website (https://www.lifelines.nl/researcher/how-to-apply/apply-here). Access to the Lifelines NEXT Project data will be granted to all qualified researchers and will be governed by the provisions laid out in the LLNEXT Data Access Agreement: https://groningenmicrobiome.org/?page_id=2598. This access procedure is in place to ensure that the data is requested solely for research and scientific purposes, in compliance with the informed consent signed by Lifelines NEXT participants. Scripts and other software central to this manuscript is available on GitHub (https://github.com/molgenis/PGx-passport-pilot/ and https://github.com/molgenis/asterix). Other analyses of genotype data and publicly available reference data is performed using standard bioinformatics practices, for which the code is made available upon request.