| Autor: |
Espregueira Themudo G; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. gethemudo@gmail.com.; 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. gethemudo@gmail.com., Leerschool AR; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Complex Genetics, Maastricht University, PO Box 616 6200, MD, Maastricht, The Netherlands., Rodriguez-Proano C; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Clinical Laboratory, Ambulatory Clinical Surgical Center and Day Hospital 'El Batán', Quito, Ecuador., Christiansen SL; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Andersen JD; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Busch JR; Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Christensen MR; Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Banner J; Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Morling N; Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. |
| Abstrakt: |
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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