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Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study

Neuropsychopharmacology (2024)Cite this article

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Abstract

Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively associated with prescribed (standardized) antipsychotic dose (beta(SE) = 0.0435(0.009), p = 0.0006) and antipsychotic polypharmacy defined as taking ≥2 antipsychotics (OR = 1.10, CI = 1.05–1.21, p = 0.0073). The direction of effect was similar in all five independent cohorts. These findings indicate that genotypes may aid clinically relevant decisions on individual patients´ antipsychotic treatment. Further, the findings illustrate how real-world data have the potential to generate results needed for future precision medicine approaches in psychiatry.

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Fig. 1
Fig. 2: Association between schizophrenia polygenic risk score (PRS) and standardized antipsychotic dosage (DDD method) across all antipsychotics in five independent cohorts.
Fig. 3: Forest plots showing the association between schizophrenia polygenic risk score (PRS) and antipsychotic polypharmacy (defined as taking ≥2 antipsychotics) in five independent cohorts, as well as meta-analyzed across these cohorts.

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Data availability

The GWAS summary statistics included in this study are publicly available. Data from the five cohorts can be made available upon request and with appropriate data transfer agreements. Due to national personal data protection regulations, raw data cannot be shared.

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Acknowledgements

This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT). Computations were also performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway (NS9666S) and the High-Performance Computing Center of University of Tartu. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 964874. We also acknowledge support from the Research Council of Norway (296030, 223273), from the US NIMH (grant R01 MH123724), the Estonian Research Council (PRG184), and the Swedish Research Council (grant number 2021-02732). We acknowledge the Estonian Biobank Research Team (Andres Metspalu, Tõnu Esko, Reedik Mägi, Mari Nelis and Georgi Hudjashov). We want to acknowledge the participants and investigators of FinnGen study. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious® services (https://site.fingenious.fi/en/) managed by FINBB.

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Author notes

  1. Lists of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. NORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Elise Koch, Robert L. Smith, Piotr Jaholkowski, Nils Eiel Steen, Olav B. Smeland, Kevin S. O’Connell & Ole A. Andreassen

  2. Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland

    Anders Kämpe, Juulia Partanen & Aarno Palotie

  3. Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia

    Maris Alver & Lili Milani

  4. deCODE Genetics/Amgen, Reykjavík, Iceland

    Sindri Sigurðarson, Guðmundur Einarsson, Hreinn Stefánsson & Kári Stefánsson

  5. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway

    Robert L. Smith & Espen Molden

  6. Niuvanniemi Hospital, Kuopio, Finland

    Heidi Taipale & Markku Lähteenvuo

  7. Department of Clinical Neuroscience, Division of Insurance Medicine, Karolinska Institutet, Stockholm, Sweden

    Heidi Taipale

  8. School of Pharmacy, University of Eastern Finland, Kuopio, Finland

    Heidi Taipale

  9. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Srdjan Djurovic

  10. NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

    Srdjan Djurovic

  11. Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway

    Espen Molden

  12. Faculty of Medicine, University of Iceland and Department of Psychiatry, Landspitali, National University Hospital, Reykjavík, Iceland

    Engilbert Sigurdsson

  13. Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia

    Lili Milani

  14. KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway

    Ole A. Andreassen

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  1. Elise Koch
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Consortia

FinnGen

Estonian Biobank Research Team

Contributions

OA, KO, and EK conceived the study and were involved in study design. EK, SS, AK, MA, GE, and JP conducted analyses. EK drafted the initial manuscript. All authors (including banner authors of the Estonian Biobank Research team and FinnGen) contributed to data interpretation and editing of the manuscript.

Corresponding authors

Correspondence to Elise Koch or Ole A. Andreassen.

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Competing interests

OAA reported grants from Stiftelsen Kristian Gerhard Jebsen, South-East Regional Health Authority, Research Council of Norway, and European Union’s Horizon 2020 during the conduct of the study; personal fees from cortechs.ai (stock options), Lundbeck (speaker’s honorarium), and Sunovion (speaker’s honorarium) and Janssen (speaker’s honorarium) outside the submitted work. HT reports personal fees from Gedeon Richter, Janssen, Lundbeck and Otsuka, and grants from Eli Lilly and Janssen, outside of the submitted work. No other disclosures were reported.

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Koch, E., Kämpe, A., Alver, M. et al. Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-023-01792-0

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