Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

iPSYCH,

doi:10.1016/j.biopsych.2021.02.972

Cited by 79 publications

(41 citation statements)

References 95 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overlaying SZ-associated genes with the transcriptomic profile of different cellular components of the NVU at distinct neurodevelopmental stages could shed lights on particular cells, cellular states, and molecular pathways being altered during SZ etiology. Additionally, the sex of the patients should also be taken into account when evaluating BBB performance, due to potential sex interactions with brain barrier integrity and permeability in SZ [91 ▪ ,93 ▪ ,96 ▪ ,101].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Brain vasculature disturbance in schizophrenia

Puvogel

Palma

Sommer

2022

Current Opinion in Psychiatry

View full text Add to dashboard Cite

Purpose of reviewThe vascular hypothesis of schizophrenia (SZ) postulates that brain endothelial dysfunction contributes to brain pathophysiology. This review discusses recent evidence for and against this hypothesis, including data related to blood–brain barrier (BBB), brain endothelium, and brain blood supply, to provide a critical weighed update.Recent findingsDifferent studies report a consistent proportion of SZ patients showing increased BBB permeability, reflected by higher levels of albumin in the cerebral spinal fluid. Of note, this was not a result of antipsychotic medication. The high inflammatory profile observed in some SZ patients is strongly associated with increased BBB permeability to circulating immune cells, and with more severe cognitive deficiencies. Also, sex was found to interact with BBB integrity and permeability in SZ. The strongest independent genetic association with SZ has been identified in FZD1, a hypoxia-response gene that is 600-fold higher expressed in early development endothelium as compared to adult brain endothelium. Regarding brain blood supply, there is evidence to suggest alterations in proper brain perfusion in SZ. Nonetheless, ex-vivo experiments suggested that widely used antipsychotics favor vasoconstriction; thus, alterations in cerebral perfusion might be related to the patients′ medication.SummaryIn some patients with SZ, a vulnerable brain endothelium may be interacting with environmental stressors, such as inflammation or hypoxia, converging into a more severe SZ symptomatology. Gene expression and performance of human brain endothelium could vary along with development and the establishment of the BBB; therefore, we encourage to investigate its possible contribution to SZ considering this dynamic context.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In 2021, a GWAS assessed interactions between sex and SZ genetic risk (33,403 SZ and 109,946 control subjects). The strongest gene-sex interaction for SZ was found in a locus harboring the gene MOCOS , a gene predominantly expressed in BECs [91 ▪ ].…”

Section: Introductionmentioning

confidence: 99%

Brain vasculature disturbance in schizophrenia

Puvogel

Palma

Sommer

2022

Current Opinion in Psychiatry

View full text Add to dashboard Cite

show abstract

“…Some genetic studies have suggested gender-specific differences in the etiology and pathogenesis of SCZ (Li et al 2016). Recently, two genome-wide genotype-by-sex analyses of neuropsychiatric disorders have found that genes that have sex-dependent effects were enriched for the neuron-and synapse-related sets (Blokland et al 2021;Martin et al 2021). Both candidate gene studies and GWAS in SCZ have reported that the sex-specific effects were primarily found among females (Goldstein et al 2013).…”

Section: Discussionmentioning

confidence: 99%

An association study of the HSPA8 gene polymorphisms with schizophrenia in a Polish population

Kowalczyk

Owczarek

Suchanek-Raif

et al. 2022

Cell Stress and Chaperones

View full text Add to dashboard Cite

Heat shock cognate 70 (HSC70/HSPA8) is considered to be a promising candidate gene for schizophrenia (SCZ) due to its many essential functions and potential neuroprotective properties in the CNS (e.g., HSC70 is involved in the turnover of the synaptic proteins, synaptic vesicle recycling, and neurotransmitter homeostasis). An alteration in the expression of HSPA8 in SCZ has been reported. This implies that the genetic variants of HSPA8 might contribute to schizophrenia pathogenesis. The present study attempted to determine whether HSPA8 polymorphisms are associated with a susceptibility to schizophrenia or whether they have an impact on the clinical parameters of the disease in a Polish population. A total of 1066 participants (406 patients and 660 controls) were recruited for the study. Five SNPs of the HSPA8 gene (rs2236659, rs1136141, rs10892958, rs1461496, and rs4936770) were genotyped using TaqMan assays. There were no differences in the allele or genotype distribution in any of the SNPs in the entire sample. We also did not find any HSPA8 haplotype-specific associations with SCZ. A gender stratification analysis revealed that an increasing risk of schizophrenia was associated with the rs1461496 genotype in females (OR: 1.68, p < 0.05) in the recessive model. In addition, we found novel associations between HSPA8 SNPs (rs1136141, rs1461496, and rs10892958) and the severity of the psychiatric symptoms as measured by the PANSS. Further studies with larger samples from various ethnic groups are necessary to confirm our findings. Furthermore, studies that explore the functional contribution of the HSPA8 variants to schizophrenia pathogenesis are also needed.

show abstract

“…Furthermore, TRYCATs themselves seem to be regulated brain-speci cally (Badawy, 2017) and vary in their ability to pass the brain-blood barrier (Fukui et al, 1991, Marx, Lane, et al, 2021. Recently, in a secondary analysis of the SCZ dataset of the Psychiatric Genomic Consortium (PGC), an interaction (rs13265509, p = 1.1×10 − 7 ) in a locus containing the IDO2 (Indoleamine 2,3-dioxygenase 2) gene, which also plays a role in the kynurenine pathway, was reported to be associated with gene-sex interaction in SCZ (Blokland et al, 2022). Therefore, the contribution of the kynurenine pathway to pathomechanisms in mental illnesses seems to be complex and as well risk gene variants as different organ systems might be involved.…”

Section: Discussionmentioning

confidence: 99%

Peripheral metabolites of the kynurenine pathway are decreased in serious mental illness and show phase-specific differences in bipolar disorder patients

Brum

Nieberler

Kehrwald

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background Previous studies have linked disturbances in the kynurenine pathway, responsible for the main catabolism of tryptophan and a key regulator of the immune system, to mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). However, the relationship between tryptophan catabolism and the presentation of psychiatric disorders seems to be rather complex, as up to now results have mostly been inconsistent or even contradictory. In this study, we measured plasma levels of tryptophan catabolites (TRYCATs: tryptophan, kynurenine, kynurenic acid and quinolinic acid) in a sample of in total 175 participants consisting of individuals suffering from an acute disease episode seeking inpatient treatment as well as healthy controls (HC) to investigate whether individual metabolites could serve as a biomarker for differential diagnosis. Results Significantly decreased levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid were found in the patient group as a whole. This was mainly driven by the difference between BD patients and HC. Specifically, the manic symptom domain in manic and mixed phase BD patients displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between the psychiatric disorders disqualifying TRYCATs as biomarkers for differential diagnosis. None of the assessed potential demographic or pharmaceutical confounding factors revealed a significant correlation to TRYCAT concentrations. Upon reaching (partial) remission, the changes in TRYCAT levels partially normalized in the patient group. Conclusions Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD. Although we cannot prove a causal relationship, underlying mechanisms might include pro-inflammatory states in the central nervous system and/or increased neurotoxicity contributing to the immune assault. Also considering the manifold, but inconsistent previous analyses regarding TRYCAT concentrations in psychiatric disease, larger, cross-sectional and longitudinal studies will be needed for detangling the mystery about the role the tryptophan catabolism plays in the pathophysiology of mental disorders and for answering the burning question if it might constitute a possible therapeutic target in the future.

show abstract

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Cited by 79 publications

References 95 publications

Brain vasculature disturbance in schizophrenia

Brain vasculature disturbance in schizophrenia

An association study of the HSPA8 gene polymorphisms with schizophrenia in a Polish population

Peripheral metabolites of the kynurenine pathway are decreased in serious mental illness and show phase-specific differences in bipolar disorder patients

Contact Info

Product

Resources

About