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Targeted exon sequencing in deceased schizophrenia patients in Denmark

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Abstract

Schizophrenia patients have higher mortality rates and lower life expectancy than the general population. However, forensic investigations of their deaths often fail to determine the cause of death, hindering prevention. As schizophrenia is a highly heritable condition and given recent advances in our understanding of the genetics of schizophrenia, it is now possible to investigate how genetic factors may contribute to mortality. We made use of findings from genome-wide association studies (GWAS) to design a targeted panel (PsychPlex) for sequencing of exons of 451 genes near index single nucleotide polymorphisms (SNPs) identified with GWAS. We sequenced the DNA of 95 deceased schizophrenia patients included in SURVIVE, a prospective, autopsy-based study of mentally ill persons in Denmark. We compared the allele frequencies of 1039 SNPs in these cases with the frequencies of 2000 Danes without psychiatric diseases and calculated their deleteriousness (CADD) scores. For 81 SNPs highly associated with schizophrenia and CADD scores above 15, expression profiles in the Genotype-Tissue Expression (GTEx) Project indicated that these variants were in exons, whose expressions are increased in several types of brain tissues, particularly in the cerebellum. Molecular pathway analysis indicated the involvement of 163 different pathways. As for rare SNP variants, most variants were scored as either benign or likely benign with an average of 17 variants of unknown significance per individual and no pathogenic variant. Our results highlight the potential of DNA sequencing of an exon panel to discover genetic factors that may be involved in the development of schizophrenia.

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Acknowledgements

We would like to thank the next-of-kin of study participants for providing consent for inclusion in this study.

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Authors and Affiliations

  1. Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Gonçalo Espregueira Themudo, Anna-Roos Leerschool, Carla Rodriguez-Proano, Sofie Lindgren Christiansen, Jeppe Dyrberg Andersen & Niels Morling

  2. CIIMAR - Interdisciplinary Centre of Marine and Environmental Research of the University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208, Matosinhos, Portugal

    Gonçalo Espregueira Themudo

  3. Department of Complex Genetics, Maastricht University, PO Box 616 6200, MD, Maastricht, The Netherlands

    Anna-Roos Leerschool

  4. Clinical Laboratory, Ambulatory Clinical Surgical Center and Day Hospital “El Batán”, Quito, Ecuador

    Carla Rodriguez-Proano

  5. Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Johannes Rødbro Busch, Martin Roest Christensen & Jytte Banner

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  1. Gonçalo Espregueira Themudo
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  9. Niels Morling
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Correspondence to Gonçalo Espregueira Themudo.

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The study was approved by the Danish National Research Ethics Board (case number: 1305373) and the National Danish Data Protection Agency (case number: SUND-2016-06). The study was carried out in compliance with the Helsinki Declaration.

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Supplementary Table 1.

List of molecular pathways identified in Reactome of genes associated with schizophrenia in this study. Included are pathway Reactome identifiers, names, number of entities found, total number of entities in that pathway, the ratios of found/total entities, the p-values, and False Discovery Rates (FDR) for the entities found, number of reactions found, in total, and their ratio, names of the submitted entities found, and identifiers of the reactions found. (XLSX 31 kb)

Supplementary Table 2.

Variants of unknown significance identified in 88 cases according to the ACMG guidelines. (XLSX 1050 kb)

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Espregueira Themudo, G., Leerschool, AR., Rodriguez-Proano, C. et al. Targeted exon sequencing in deceased schizophrenia patients in Denmark. Int J Legal Med 134, 135–147 (2020). https://doi.org/10.1007/s00414-019-02212-z

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