Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Purpose We constructed a CYP2D6 copy-number imputation panel by combining copy-number information to GWAS chip data. In addition, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. Methods We combined GWAS chip and CYP2D6 copy-number variation (CNV) data from the Breast Cancer Pain Genetics study (BrePainGen) to construct an imputation panel (N=902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9,262 non-related individuals passing genotype data quality control procedures. The panel performance was evaluated by genotyping the CNV from a subset (N=297) of SUPER-Finland participants. Results CYP2D6 CNV was imputed correctly in 272 (92%) individuals. Sensitivity and specificity for detecting a duplication were 0.986 and 0.946, respectively. Sensitivity and specificity for detecting a deletion using imputation were 0.886 and 0.966, respectively. Based on imputation, the frequency of a CYP2D6 duplication and deletion in the whole SUPER-Finland sample with 9,262 non-related individuals passing quality control were 8.5% and 2.7%, respectively. We confirm the higher frequency of CYP2D6 ultrarapid metabolizers in Finland compared with non-Finnish Europeans. Additionally, we confirm a 21-fold enrichment of the UGT1A1 decreased function variant rs4148323 (also known as 211G>A, G71R or UGT1A1 *6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. Conclusion Our results demonstrate that imputation of CYP2D6 CNV is possible. The methodology is not accurate enough to be used in clinical decision making, but it enables studying CYP2D6 in large biobanks with genome-wide data. In addition, it allows for researchers to recontact patients with certain pharmacogenetic variations through biobanks. We show that bottle-necked populations may have pharmacogenetically important variants with allele frequencies very different from the main ancestral group. Future studies should assess whether these differences are large enough to cause clinically significant changes in trial results across different ancestral groups. ### Competing Interest Statement Markku Lähteenvuo is a board member of Genomi Solutions ltd. and Nursie Health ltd., has received honoraria from Sunovion ltd., Orion Pharma ltd., Otsuka ltd and Janssen-Cilag. Ari Ahola-Olli is a part-time employee at Abomics, a company offering pharmacogenetic consultation services and ICT solutions. Part of the salaries of Mari Kaunisto and Risto Kajanne is covered by a large Finnish biobank study FinnGen, funded by twelve international pharmaceutical companies (Abbvie, AstraZeneca, Biogen, Celgene, Genentech, GSK, Janssen, Maze Therapeutics, Merck/MSD, Novartis, Pfizer and Sanofi) and Business Finland. The other authors declare no competing interests. ### Funding Statement The SUPER-Finland sample collection was funded by The Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Boston, USA. Katja Häkkinen has received funding from the Ministry of Social Affairs and Health Finland, through the developmental fund for Niuvanniemi Hospital, Kuopio, Finland, The Finnish Cultural Foundation, Helsinki, Finland, The Finnish Foundation for Psychiatric Research, Helsinki, Finland, The Social Insurance Institution of Finland, Helsinki, Finland and The Emil Aaltonen Foundation, Tampere, Finland. Markku Lähteenvuo has received funding from The Finnish Medical Foundation, Helsinki, Finland and Emil Aaltonen Foundation, Tampere, Finland. Kimmo Suokas has received funding from The Jalmari and Rauha Ahokas Foundation, Helsinki, Finland and The Finnish Foundation for Psychiatric Research, Helsinki, Finland. Mikko Niemi has received funding from Sigrid Jusélius Foundation, Helsinki, Finland. Ari Ahola-Olli has received funding from The Orion Research Foundation, Espoo, Finland, The Juho Vainio Foundation, Helsinki, Finland and The Finnish Post Doc Pool. ### Author Declarations 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 SUPER-Finland study was given a favorable ethics statement (202/13/03/00/15) by the Coordinating Ethics Committee of the The Hospital District of Helsinki and Uusimaa (HUS). The BrePainGen study was approved by the Coordinating Ethics Committee (136/E0/2006) and the Ethics Committee of the Department of Surgery (Dnro 148/E6/05) of the Hospital District of Helsinki and Uusimaa (HUS). Written informed consent was obtained from each participant prior to inclusion in both of the studies. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data is available from THL biobank when released from original study