Search

Private companies have begun offering services to allow parents undergoing in-vitro fertilisation to screen embryos for genetic risk of complex diseases, including psychiatric disorders. This procedure, called polygenic embryo screening, raises several difficult scientific and ethical issues, as discussed in this Personal View. Polygenic embryo screening depends on the statistical properties of polygenic risk scores, which are complex and not well studied in the context of this proposed clinical application. The clinical, social, and ethical implications of polygenic embryo screening have barely been discussed among relevant stakeholders. To our knowledge, the International Society of Psychiatric Genetics is the first professional biomedical organisation to issue a statement regarding polygenic embryo screening. For the reasons discussed in this Personal View, the Society urges caution and calls for additional research and oversight on the use of polygenic embryo screening., Competing Interests: Declaration of interests JA has received consulting fees from 23andme. TS has received consulting fees from Baylor College of Medicine. LB is listed as an inventor on Issued US Patent 8,080,371,“Markers for Addiction”. All authors were members of the Ethics Committee of the International Society of Psychiatric Genetics at the time of writing., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) has been previously associated with clinical signs of premature aging, including accelerated epigenetic aging in blood and brain, and a steeper age-related decline in cognitive function. However, the clinical drivers and cognitive correlates of epigenetic aging in BD are still unknown. We aimed to investigate the relationship between multiple measures of epigenetic aging acceleration with clinical, functioning, and cognitive outcomes in patients with BD and controls. Blood genome-wide DNA methylation levels were measured in BD patients (n = 153) and matched healthy controls (n = 50) with the Infinium MethylationEPIC BeadChip (Illumina). Epigenetic age estimates were calculated using an online tool, including the recently developed lifespan predictor GrimAge, and analyzed with generalized linear models controlling for demographic variables and blood cell proportions. BD was significantly associated with greater GrimAge acceleration (AgeAccelGrim, β=0.197, p = 0.009), and significant group-dependent interactions were found between AgeAccelGrim and blood cell proportions (CD4+ T-lymphocytes, monocytes, granulocytes, and B-cells). Within patients, higher AgeAccelGrim was associated with worse cognitive function in multiple domains (short-term affective memory (β=-0.078, p = 0.030), short-term non-affective memory (β=-0.088, p = 0.018), inhibition (β=0.064, p = 0.046), and problem solving (β=-0.067, p = 0.034)), age of first diagnosis with any mood disorder (β=-0.076, p = 0.039) or BD (β=-0.102, p = 0.016), as well as with current non-smoking status (β=-0.392, p < 0.001). Overall, our findings support the contribution of epigenetic factors to the aging-related cognitive decline and premature mortality reported in BD patients, with an important driving effect of smoking in this population., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest regarding this manuscript., (Copyright © 2022. Published by Elsevier B.V.)

Bipolar disorder (BD) has been associated with immune changes, and yet their underlying mechanisms are still not fully understood. Here, we review the current state of the field, concerning the inflammatory alterations observed in the periphery and in the central nervous system, followed by a discussion of potential underlying mechanisms. We focus mainly on recently proposed mechanisms including the role of the gut-brain axis, the release of damage-associated molecular patterns (DAMPs), and the genetic and epigenetic mechanisms. BD immunology is an evolving field and current studies indicate this disease is more than a brain disorder, and it can be conceptualized as a multi-system condition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Metabolic syndrome (MetS) is seen more frequently in persons with schizophrenia than in the general population, and these metabolic abnormalities are further aggravated by second generation antipsychotic (SGA) drugs. Although the underlying mechanisms responsible for the increased prevalence of MetS among patients under SGA treatment are not well understood, alterations in mitochondria function have been implicated. We performed a comprehensive evaluation of the role of mitochondrial dysfunction in the pathophysiology of drug-induced MetS in schizophrenia. We found a downregulation in genes encoding subunits of the electron transport chain complexes (ETC), enzyme activity, and mitochondrial dynamics in peripheral blood cells from patients at high-risk for MetS. Additionally, we evaluated several markers of energy metabolism in lymphoblastoid cell lines from patients with schizophrenia and controls following exposure to antipsychotics. We found that the high-risk drugs clozapine and olanzapine induced a general down-regulation of genes involved in the ETC, as well as decreased activities of the corresponding enzymes, ATP levels and a significant decrease in all the functional parameters of mitochondrial oxygen consumption in cells from patients and controls. We also observed that the medium-risk SGA quetiapine decreased oxygen consumption and respiratory control ratio in controls and patients. Additionally, clozapine and olanzapine induced a downregulation of Drp1 and Mfn2 both in terms of mRNA and protein levels. Together, these data suggest that an intrinsic defect in multiple components of oxidative metabolism may contribute to the increased prevalence of MetS in patients under treatment with SGAs known to cause risk for MetS., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Lithium is the most commonly prescribed medication for the treatment of bipolar disorder (BD), yet the mechanisms underlying its beneficial effects are still unclear. We aimed to compare the effects of lithium treatment in lymphoblastoid cell lines (LCLs) from BD patients and controls. LCLs were generated from sixty-two BD patients (based on DSM-IV) and seventeen healthy controls matched for age, sex, and ethnicity. Patients were recruited from outpatient clinics from February 2012 to October 2014. LCLs were treated with 1mM lithium for 7 days followed by microarray gene expression assay and validation by real-time quantitative PCR. Baseline differences between groups, as well as differences between vehicle- and lithium-treated cells within each group were analyzed. The biological significance of differentially expressed genes was examined by pathway enrichment analysis. No significant differences in baseline gene expression (adjusted p-value < 0.05) were detected between groups. Lithium treatment of LCLs from controls did not lead to any significant differences. However, lithium altered the expression of 236 genes in LCLs from patients; those genes were enriched for signaling pathways related to apoptosis. Among those genes, the alterations in the expression of PIK3CG, SERP1 and UPP1 were validated by real-time PCR. A significant correlation was also found between circadian functioning and CEBPG and FGF2 expression levels. In summary, our results suggest that lithium treatment induces expression changes in genes associated with the apoptosis pathway in BD LCLs. The more pronounced effects of lithium in patients compared to controls suggest a disease-specific effect of this drug., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Background: Although genetic factors are known to play an important role in schizophrenia, the identification of genes involved in this disorder has remained elusive. The neuregulin 1 gene is among the few candidate genes to have been implicated in schizophrenia susceptibility in several populations. However, no causal mutations within this gene have been identified., Methods: In attempts to identify polymorphisms within the neuregulin 1 gene, we performed DNA sequencing using 12 subjects with a history of psychosis from the Central Valley of Costa Rica. DNA genotyping and association studies were then performed in an extended cohort of 142 affected individuals and their relatives from the same population., Results: We identified a novel missense mutation (Val to Leu) in exon 11, which codes for the transmembrane region of the neuregulin 1 protein. Association analysis by the Family Based Association Test (FBAT) revealed that this mutation is associated with psychosis (p = .0049) and schizophrenia (p = .0191) in this population., Conclusions: We report the finding of a missense mutation in the neuregulin 1 gene associated with schizophrenia. Additional analyses of an independent sample as well as detailed functional studies should be performed to determine the relevance of this novel polymorphism to the pathophysiology of schizophrenia.