Genetic investigations of 100 inherited cardiac disease-related genes in deceased individuals with schizophrenia.

Cardiac diseases and sudden cardiac death (SCD) are more prevalent in individuals diagnosed with schizophrenia compared to the general population, with especially coronary artery disease (CAD) as the major cardiovascular cause of death. Antipsychotic medications, genetics, and lifestyle factors may contribute to the increased SCD in individuals with schizophrenia. The role of antipsychotic medications and lifestyle factors have been widely investigated, while the genetic predisposition to inherited cardiac diseases in schizophrenia is poorly understood. In this study, we examined 100 genes associated with inherited cardiomyopathies and cardiac channelopathies in 97 deceased individuals diagnosed with schizophrenia for the prevalence of genetic variants associated with SCD. The deceased individuals had various causes of death and were included in the SURVIVE project, a prospective, autopsy-based study of mentally ill individuals in Denmark. This is the first study of multiple inherited cardiac disease-related genes in deceased individuals with diagnosed schizophrenia to shed light on the genetic predisposition to SCD in individuals with schizophrenia. We found no evidence for an overrepresentation of rare variants with high penetrance in inherited cardiac diseases, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG) consensus guidelines. However, we found that the deceased individuals had a statistically significantly increased polygenic burden caused by variants in the investigated heart genes compared to the general population. This indicates that common variants with smaller effects in heart genes may play a role in schizophrenia.

Targeted exon sequencing in deceased schizophrenia patients in Denmark.

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.

Elevated levels of 8-oxoGuo and 8-oxodG in individuals with severe mental illness - An autopsy-based study.

Elevated systemic oxidative stress levels of 8-oxoGuo and 8-oxodG have been reported in individuals with severe mental illness (SMI). As no previous studies have addressed the link between local levels of 8-oxoGuo and 8-oxodG in the central nervous system (CNS), measured in cerebrospinal fluid (CSF), and urinary systemic levels, we employed autopsy-based material to elucidate this aspect. Additionally, we investigated the impact of 8-oxoGuo and 8-oxodG levels on the prevalence of somatic co-morbidities. Based on post mortem samples from deceased individuals with SMI (N = 107), we found significantly elevated urinary levels of both 8-oxoGuo and 8-oxodG compared to mentally healthy living controls. While we found an association between urinary and CSF 8-oxodG levels (r = 0.50, P < 0.001), a similar correlation was not evident for 8-oxoGuo (r = 0.15, P = 0.16). Additionally, the two r-values were significantly different (P < 0.001). Neither marker in urine or CSF was associated with obesity-related variables, metabolic syndrome or type 2 diabetes. The post mortem interval did not affect the results, but the agonal phase seemingly introduced bias. This study provided novel insights into the cellular oxidative stress levels in individuals with SMI. We demonstrated that increased oxidative stress locally and systemically is correlated and is a clear phenomenon in SMI. Although post mortem measurements contain some weaknesses, our study indicates DNA as the main site of oxidative stress modifications in the CNS in SMI. This may provide novel opportunities for treatment modalities. Additionally, our study demonstrated the applicability of post mortem material investigating systemic and local 8-oxoGuo and 8-oxodG levels.

Establishing post mortem criteria for the metabolic syndrome: an autopsy based cross-sectional study.

BACKGROUND: Individuals who suffer from mental illness are more prone to obesity and related co-morbidities, including the metabolic syndrome. Autopsies provide an outstanding platform for the macroscopic, microscopic and molecular-biological investigation of diseases. Autopsy-based findings may assist in the investigation of the metabolic syndrome. To utilise the vast information that an autopsy encompasses to elucidate the pathophysiology behind the syndrome further, we aimed to both develop and evaluate a method for the post mortem definition of the metabolic syndrome. METHODS: Based on the nationwide Danish SURVIVE study of deceased mentally ill, we established a set of post mortem criteria for each of the harmonized criteria of the metabolic syndrome. We based the post mortem (PM) evaluation on information from the police reports and the data collected at autopsy, such as anthropometric measurements and biochemical and toxicological analyses (PM information). We compared our PM evaluation with the data from the Danish health registries [ante mortem (AM) information, considered the gold standard] from each individual. RESULTS: The study included 443 deceased individuals (272 male and 171 female) with a mean age of 50.4 (± 15.5) years and a median (interquartile range) post mortem interval of 114 (84-156) hours. We found no significant difference when defining the metabolic syndrome from the PM information in comparison to the AM information (P = 0.175). The PM evaluation yielded a high specificity (0.93) and a moderate sensitivity (0.63) with a moderate level of agreement compared to the AM evaluation (Cohen's κ = 0.51). Neither age nor post mortem interval affected the final results. CONCLUSIONS: Our model of a PM definition of the metabolic syndrome proved reliable when compared to the AM information. We believe that an appropriate estimate of the prevalence of the metabolic syndrome can be established post mortem. However, while neither the PM nor the AM information is exhaustive in terms of defining an individual's health status, a superlative estimate may be obtained by combining the PM and the AM information. With this model, we open up the possibility of utilising autopsy data for future studies of the metabolic syndrome.