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.

Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation.

Large deletions at chromosome 22q11.2 are known to cause severe clinical conditions collectively known as 22q11.2 deletion syndrome. Notwithstanding the pathogenicity of these deletions, affected individuals are typically diagnosed in late childhood or early adolescence, and little is known of the molecular signaling cascades and biological consequences immediately downstream of the deleted genes. Here, we used targeted metabolomics to compare neonatal dried blood spot samples from 203 individuals clinically identified as carriers of a deletion at chromosome 22q11.2 with 203 unaffected individuals. A total of 173 metabolites were successfully identified and used to inform on systemic dysregulation caused by the genomic lesion and to discriminate carriers from non-carriers. We found 84 metabolites to be differentially abundant between carriers and non-carriers of the 22q11.2 deletion. A predictive model based on all 173 metabolites achieved high Accuracy (89%), Area Under the Curve (93%), F1 (88%), Positive Predictive Value (94%), and Negative Predictive Value (84%) with tyrosine and proline having the highest individual contributions to the model as well as the highest interaction strength. Targeted metabolomics provides insight into the molecular consequences possibly contributing to the pathology underlying the clinical manifestations of the 22q11 deletion and is an easily applicable approach to first-pass screening for carrier status of the 22q11 to prompt subsequent verification of the genomic diagnosis.

Associations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors.

Schizophrenia is a heterogeneous disorder, exhibiting variability in presentation and outcomes that complicate treatment and recovery. To explore this heterogeneity, we leverage the comprehensive Danish health registries to conduct a prospective, longitudinal study from birth of 5432 individuals who would ultimately be diagnosed with schizophrenia, building individual trajectories that represent sequences of comorbid diagnoses, and describing patterns in the individual-level variability. We show that psychiatric comorbidity is prevalent among individuals with schizophrenia (82%) and multi-morbidity occur more frequently in specific, time-ordered pairs. Three latent factors capture 79% of variation in longitudinal comorbidity and broadly relate to the number of co-occurring diagnoses, the presence of child versus adult comorbidities and substance abuse. Clustering of the factor scores revealed five stable clusters of individuals, associated with specific risk factors and outcomes. The presentation and course of schizophrenia may be associated with heterogeneity in etiological factors including family history of mental disorders.

Next-generation biology: Sequencing and data analysis approaches for non-model organisms.

As sequencing technologies become more affordable, it is now realistic to propose studying the evolutionary history of virtually any organism on a genomic scale. However, when dealing with non-model organisms it is not always easy to choose the best approach given a specific biological question, a limited budget, and challenging sample material. Furthermore, although recent advances in technology offer unprecedented opportunities for research in non-model organisms, they also demand unprecedented awareness from the researcher regarding the assumptions and limitations of each method. In this review we present an overview of the current sequencing technologies and the methods used in typical high-throughput data analysis pipelines. Subsequently, we contextualize high-throughput DNA sequencing technologies within their applications in non-model organism biology. We include tips regarding managing unconventional sample material, comparative and population genetic approaches that do not require fully assembled genomes, and advice on how to deal with low depth sequencing data.

Molecular epidemiology of circulating highly pathogenic avian influenza (H5N1) virus in chickens, in Bangladesh, 2007-2010.

Bangladesh has been severely hit by highly pathogenic avian influenza H5N1 (HPAI-H5N1). However, little is known about the genetic diversity and the evolution of the circulating viruses in Bangladesh. In the present study, we analyzed the hemagglutinin gene of 30 Bangladeshi chicken isolates from 2007 through 2010. We analyzed the polybasic amino acid sequence motif of the cleavage site and amino acid substitution pattern. Phylogenetic history was reconstructed using neighbor-joining and Bayesian time-scaled methods. In addition, we used Mantel correlation tests to analyze the relation between genetic relatedness and spatial and temporal distances. Neighbor-joining phylogeography revealed that virus circulating in Bangladesh from 2007 through 2010 belonged to clade 2.2. The results suggest that clade 2.2 viruses are firmly entrenched and have probably become endemic in Bangladesh. We detected several amino acid substitutions, but they are not indicative of adaptation toward human infection. The Mantel correlation test confirmed significant correlation between genetic distances and temporal distances between the viruses. The Bayesian tree shows that isolates from waves 3 and 4 derived from a subgroup of isolates from the previous waves grouping with a high posterior probability (pp=1.0). This indicates the possibility of formation of local subclades. One surprising finding of spatio-temporal analysis was that genetically identical virus caused independent outbreaks over a distance of more than 200 km and within 14 days of each other. This might indicate long distance dispersal through vectors such as migratory birds and vehicles, and challenges the effectiveness of movement restriction around 10 km radius of an outbreak. The study indicates possible endemicity of the clade 2.2 HPAI-H5N1 virus in Bangladesh. Furthermore, the formation of a subclade capable of transmission to humans cannot be ruled out. The findings of this study might provide valuable information for future surveillance, prevention and control programme.

Persistent spatial clusters of plasmacytosis among Danish mink farms.

Aleutian disease (Plasmacytosis) is caused by the Aleutian mink disease virus (AMDV), an autonomous parvovirus and affects many mustelid species, including the American mink (Neovisonvison). In Denmark, an eradication program reduced the prevalence of test-positive farms from 100% in 1976 to 15% in 1996. Nevertheless, the disease persists in the Vendsyssel district of Northern Jutland, despite the eradication efforts. In this study, we used spatial epidemiological analysis to test for spatial autocorrelation of the distribution of farms positive for the disease. We investigated 2375 farms in Denmark (342 of which were located in the Vendsyssel district), during the period 2000-2008. For the purpose of our study, a farm was considered positive when, on any test conducted in a year, at least three animals were tested positive. To detect spatial clusters, we performed a retrospective analysis with spatial scan statistics. We performed one analysis for each of the nine years (2000-2008). A separate analysis was conducted with only the farms in Vendsyssel included. The spatial cluster analysis revealed a significant cluster throughout the time period studied in Northern Jutland. The only exception was 2002 when an outbreak was detected in the southern part of Jutland, and not in the north. The farm-level prevalence of the disease in Denmark was highest in this year, suggesting that the outbreak in the south could have masked the persistent signal from the north; the northern cluster was still significant when analysing only the Vendsyssel populations. These results confirm that Northern Jutland continues to have a significantly higher number of cases than expected if the disease was randomly distributed.