Offspring of parents with severe mental illness are at increased risk of developing psychopathology. Identifying endophenotypic markers in high-familial-risk individuals can aid in early detection and inform development of prevention strategies. Using generalized additive mixed models, we compared age trajectories of gyrification index (GI) and sulcal morphometric measures (i.e., sulcal depth, length and width) between individuals at familial risk for bipolar disorder or schizophrenia and controls. 300 T1-weighted MRI scans were obtained of 187 individuals (53 % female, age range: 8-23 years) at familial risk for bipolar disorder (n = 80, n families=55) or schizophrenia (n = 53, n families=36) and controls (n = 54, n families=33). 113 individuals underwent two scans. Globally, GI, sulcal depth and sulcal length decreased significantly with age, and sulcal width increased significantly with age in a (near-)linear manner. There were no differences between groups in age trajectories or mean values of gyrification or any of the sulcal measures. These findings suggest that, on average, young individuals at familial risk for bipolar disorder or schizophrenia have preserved developmental patterns of gyrification and sulcal morphometrics during childhood and adolescence.
- Klíčová slova
- Bipolar disorder, Gyrification, High familial risk, Longitudinal, Offspring, Schizophrenia,
- MeSH
- bipolární porucha * patologie genetika diagnostické zobrazování MeSH
- dítě postižených rodičů MeSH
- dítě MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozková kůra * růst a vývoj patologie MeSH
- schizofrenie * patologie genetika diagnostické zobrazování MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.
- MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozková kůra diagnostické zobrazování MeSH
- neurozobrazování MeSH
- schizofrenie * genetika MeSH
- syndrom MeSH
- temenní lalok MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
BACKGROUND: Insulin-degrading enzyme (IDE) is an important gene in studies of the pathophysiology of type 2 diabetes mellitus (T2DM). Recent studies have suggested a possible link between type 2 diabetes mellitus (T2DM) and the pathophysiology of schizophrenia (SZ). At the same time, significant changes in insulin-degrading enzyme (IDE) gene expression have been found in the brains of people with schizophrenia. These findings highlight the need to further investigate the role of IDE in schizophrenia pathogenesis. METHODS: We enrolled 733 participants from the Czech Republic, including 383 patients with schizophrenia and 350 healthy controls. Our study focused on the single nucleotide polymorphism (SNP) rs2421943 in the IDE gene, which has previously been associated with the pathogenesis of Alzheimer's disease. The SNP was analyzed using the PCR-RFLP method. RESULTS: The G allele of the rs2421943 polymorphism was found to significantly increase the risk of developing SZ (p < 0.01) when a gender-based analysis showed that both AG and GG genotypes were associated with a more than 1.55 times increased risk of SZ in females (p < 0.03) but not in males. Besides, we identified a potential binding site at the G allele locus for has-miR-7110-5p, providing a potential mechanism for the observed association. CONCLUSION: Our results confirm the role of the IDE gene in schizophrenia pathogenesis and suggest that future research should investigate the relationship between miRNA and estrogen influence on IDE expression in schizophrenia pathogenesis.
- Klíčová slova
- candidate gene analyses, genetic association study, insulin-degrading enzyme (IDE), miRNA, schizophrenic disorder, single nucleotide polymorphism (SNP),
- MeSH
- Alzheimerova nemoc * genetika metabolismus MeSH
- diabetes mellitus 2. typu * epidemiologie genetika MeSH
- genotyp MeSH
- insulinasa * genetika metabolismus MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- schizofrenie * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- insulinasa * MeSH
Schizophrenia (SZ) is a highly inherited disease that affects ~0.5% of the population. The genetic and environmental factors are involved in its aetiology and they interact with each other. Combination of symptoms is unique to each patient, the disease seriously interferes with the ability to function in society and affects the mental state of the patient. In most patients, the first manifestations of SZ appear during the adolescence or early adulthood. The hypothesis that SZ origin in impaired development of the nervous system is currently widely accepted. Some studies have identified several genetic and environmental factors that increase the risk of the disease manifestation, but none of them can be considered as the only cause of SZ. The genetics of the disease is complex and in last two decades it is assumed that the cryptic rearrangements could be one of its causes. Cryptic rearrangements (microdeletions and microduplications) are the chromosomal rearrangements smaller than 3-5 Mb. Their discovery was conditioned by the development of molecular genetic and molecular cytogenetic techniques. The aberrations affect one or more genes and change the gene dose. In this article, we present the rearrangements of the regions of human chromosomes more closely associated with the onset and development of SZ. Next, the candidate genes will be presented together with their inclusion in the context of theories trying to explain the origin of SZ through some important factors (e.g. action of dopamine or glutamate or GABA, formation of dendrites and neuronal synapses, etc.).
Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
- MeSH
- alely MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci genetika MeSH
- genomika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- schizofrenie * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
IMPORTANCE: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. OBJECTIVE: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. DESIGN, SETTING, AND PARTICIPANTS: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). MAIN OUTCOMES AND MEASURES: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. RESULTS: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). CONCLUSIONS AND RELEVANCE: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.
- MeSH
- celogenomová asociační studie MeSH
- genetická predispozice k nemoci genetika MeSH
- lidé MeSH
- multifaktoriální dědičnost genetika MeSH
- psychotické poruchy * farmakoterapie MeSH
- schizofrenie * diagnóza farmakoterapie genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.
- Klíčová slova
- 2-arachidonoylglycerol (2-AG), AM251, MAM model, cannabinoid CB1 receptor, endocannabinoid system, schizophrenia,
- MeSH
- krysa rodu Rattus MeSH
- methylazoxymethanolacetát * MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- receptor kanabinoidní CB1 MeSH
- schizofrenie * chemicky indukované farmakoterapie genetika MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- methylazoxymethanolacetát * MeSH
- receptor kanabinoidní CB1 MeSH
BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
- Klíčová slova
- Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences,
- MeSH
- bipolární porucha genetika MeSH
- celogenomová asociační studie MeSH
- depresivní porucha unipolární * genetika MeSH
- endoteliální buňky MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- pohlavní dimorfismus * MeSH
- psychotické poruchy * genetika MeSH
- receptory vaskulárního endoteliálního růstového faktoru MeSH
- schizofrenie genetika MeSH
- sulfurtransferasy MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- MOCOS protein, human MeSH Prohlížeč
- receptory vaskulárního endoteliálního růstového faktoru MeSH
- sulfurtransferasy MeSH
Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
- MeSH
- bipolární porucha * farmakoterapie genetika MeSH
- deprese MeSH
- depresivní porucha unipolární * farmakoterapie genetika MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- lithium terapeutické užití MeSH
- multifaktoriální dědičnost MeSH
- rizikové faktory MeSH
- schizofrenie * farmakoterapie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Názvy látek
- lithium MeSH
Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
- Klíčová slova
- Cannabidiol, Cannabinoid CB1 receptor, DNA methylation, Dopamine D2 receptor, Epigenetics, Schizophrenia, THC,
- MeSH
- chování zvířat účinky léků MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- maternofetální výměna látek MeSH
- messenger RNA metabolismus MeSH
- metylace DNA účinky léků MeSH
- potkani Sprague-Dawley MeSH
- prefrontální mozková kůra účinky léků metabolismus MeSH
- receptor kanabinoidní CB1 genetika MeSH
- receptory dopaminu D2 genetika MeSH
- regulace genové exprese účinky léků MeSH
- schizofrenie genetika MeSH
- těhotenství MeSH
- tetrahydrokanabinol farmakologie MeSH
- zpožděný efekt prenatální expozice * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- messenger RNA MeSH
- receptor kanabinoidní CB1 MeSH
- receptory dopaminu D2 MeSH
- tetrahydrokanabinol MeSH
