Targeted exon sequencing in deceased schizophrenia patients in Denmark

  • Gonçalo Espregueira ThemudoEmail author
  • Anna-Roos Leerschool
  • Carla Rodriguez-Proano
  • Sofie Lindgren Christiansen
  • Jeppe Dyrberg Andersen
  • Johannes Rødbro Busch
  • Martin Roest Christensen
  • Jytte Banner
  • Niels Morling
Original Article


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.


Haloplex Genomics Massively parallel sequencing Molecular autopsy Schizophrenia 



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

Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

414_2019_2212_MOESM1_ESM.xlsx (32 kb)
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)
414_2019_2212_MOESM2_ESM.xlsx (1 mb)
Supplementary Table 2. Variants of unknown significance identified in 88 cases according to the ACMG guidelines. (XLSX 1050 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.CIIMAR - Interdisciplinary Centre of Marine and Environmental Research of the University of PortoMatosinhosPortugal
  3. 3.Department of Complex GeneticsMaastricht UniversityMaastrichtThe Netherlands
  4. 4.Clinical LaboratoryAmbulatory Clinical Surgical Center and Day Hospital “El Batán”QuitoEcuador
  5. 5.Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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