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1.
Nat Hum Behav ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462475

RESUMO

Genome-wide association studies (GWAS) have identified several common genetic variants influencing major depression and general cognitive abilities, but little is known about whether the two share any of their genetic aetiology. Here we investigate shared genomic architectures between major depression (MD) and general intelligence (INT) with the MiXeR statistical tool and their overlapping susceptibility loci with conjunctional false discovery rate (conjFDR), which evaluate the level of overlap in genetic variants and improve the power for gene discovery between two phenotypes. We analysed GWAS data on MD (n = 480,359) and INT (n = 269,867) to characterize polygenic architecture and identify genetic loci shared between these phenotypes. Despite non-significant genetic correlation (rg = -0.0148, P = 0.50), we observed large polygenic overlap and identified 92 loci shared between MD and INT at conjFDR < 0.05. Among the shared loci, 69 and 64 are new for MD and INT, respectively. Our study demonstrates polygenic overlap between these phenotypes with a balanced mixture of effect.

2.
Transl Psychiatry ; 11(1): 3, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33414458

RESUMO

Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

3.
Transl Psychiatry ; 10(1): 416, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257657

RESUMO

Cognitive impairments are considered core features in schizophrenia and other psychotic disorders. Cognitive impairments are, to a lesser degree, also documented in healthy first-degree relatives. Although recent studies have shown (negative) genetic correlations between schizophrenia and general cognitive ability, the association between polygenic risk for schizophrenia and individual cognitive phenotypes remains unclear. We here investigated the association between a polygenic score for schizophrenia (SCZPGS) and six well-defined cognitive domains, in addition to a composite measure of cognitive ability and a measure of premorbid intellectual ability in 731 participants with a psychotic disorder and 851 healthy controls. We also investigated the association between a PGS for general cognitive ability (COGPGS) and the same cognitive domains in the same sample. We found no significant associations between the SCZPGS and any cognitive phenotypes, in either patients with a psychotic disorder or healthy controls. For COGPGS we observed stronger associations with cognitive phenotypes in healthy controls than in participants with psychotic disorders. In healthy controls, the association between COGPGS (at the p value threshold of ≥0.01) and working memory remained significant after Bonferroni correction (ß = 0.12, p = 8.6 × 10-5). Altogether, the lack of associations between SCZPGS and COGPGS with cognitive performance in participants with psychotic disorders suggests that either environmental factors or unassessed genetic factors play a role in the development of cognitive impairments in psychotic disorders. Working memory should be further studied as an important cognitive phenotype.

5.
Front Psychiatry ; 11: 672, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754070

RESUMO

Background: Cardiovascular disease (CVD) is a major cause of premature death in patients with psychotic disorders, where dyslipidemia occurs frequently. In the pathogenesis of these serious mental disorders, a low-grade inflammation seems to be a possible contributor. Concurrently, systemic inflammation and its interplay with dyslipidemia is a central driver in the pathogenesis of CVD. We hypothesize that evaluation of atherogenic lipid ratios together with inflammatory markers reflecting different inflammatory pathways with relevance for atherogenesis, could give novel information on immune-related mechanisms involved in early CVD risk in patients with psychotic disorders. Methods: As a measure for CVD risk we calculated atherogenic lipid ratios using established sex-specific cut-offs: Total cholesterol/high-density lipoprotein; HDL-c (TC/HDL) and triglyceride/HDL-c (TG/HDL) were evaluated in 571 schizophrenia (SCZ) and 247 bipolar disorder (BD) patients, and in 99 healthy controls (HC). In addition, as a measure of low-grade inflammation, we measured fasting plasma levels of nine stable atherogenic inflammatory markers in patients (SCZ, BD) and in HC. The elevated inflammatory markers and CVD risk in patients, as reflected by TC/HDL and TG/HDL, were further assessed in multivariable analyses adjusting for comorbid cardio-metabolic risk factors. Results: A markedly higher proportion (26%-31%) of patients had increased TC/HDL and TG/HDL ratios compared with HC. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO) were higher (p<0.05, p<0.001) in patients with psychotic disorders than in HC, and hs-CRP and MPO were independently associated with atherogenic lipid ratios in the multivariable analyses. Conclusions: Our findings suggest that low-grade inflammation and abnormal neutrophil activation may cause increased CVD risk in patients with psychotic disorders. These mechanisms should be further examined to determine the potential for development of novel risk evaluation strategies.

6.
Nat Commun ; 11(1): 4016, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782260

RESUMO

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Tronco Encefálico/anatomia & histologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/metabolismo , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Homologia de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imagem por Ressonância Magnética , Herança Multifatorial , Tamanho do Órgão/genética
7.
Front Psychiatry ; 11: 642, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714224

RESUMO

The complex effects of plant cannabinoids on human physiology is not yet fully understood, but include a wide spectrum of effects on immune modulation. The immune system and its inflammatory effector pathways are recently emerging as possible causative factors in psychotic disorders. The present study aimed to investigate whether self-administered Cannabis use was associated with changes in circulating immune and neuroendocrine markers in schizophrenia (SCZ) and bipolar disorder (BD) patients. A screening of 13 plasma markers reflecting different inflammatory pathways was performed in SCZ (n = 401) and BD patients (n = 242) after subdividing each group into Cannabis user and non-user subgroups. We found that i) soluble gp130 (sgp130) concentrations were significantly elevated among Cannabis users in the SCZ group (p = 0.002) after multiple testing correction, but not in BD. ii) Nominally significant differences were observed in the levels of IL-1RA (p = 0.0059), YKL40 (p = 0.0069), CatS (p = 0.013), sTNFR1 (p = 0.031), and BDNF (p = 0.020), where these factors exhibited higher plasma levels in Cannabis user SCZ patients than in non-users. iii) These differences in systemic levels were not reflected by altered mRNA expression of genes encoding sgp130, IL-1RA, YKL40, CatS, sTNFR1, and BDNF in whole blood. Our results show that Cannabis self-administration is associated with markedly higher sgp130 levels in SCZ, but not in BD, and that this phenomenon is independent of the modulation of peripheral immune cells. These findings warrant further investigation into the potential IL-6 trans-signaling modulatory, anti-inflammatory, neuroimmune, and biobehavioral-cognitive effects of Cannabis use in SCZ.

8.
Mol Autism ; 11(1): 42, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487215

RESUMO

Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets.

9.
Bioinformatics ; 36(18): 4749-4756, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539089

RESUMO

MOTIVATION: Determining the relative contributions of functional genetic categories is fundamental to understanding the genetic etiology of complex human traits and diseases. Here, we present Annotation Informed-MiXeR, a likelihood-based method for estimating the number of variants influencing a phenotype and their effect sizes across different functional annotation categories of the genome using summary statistics from genome-wide association studies. RESULTS: Extensive simulations demonstrate that the model is valid for a broad range of genetic architectures. The model suggests that complex human phenotypes substantially differ in the number of causal variants, their localization in the genome and their effect sizes. Specifically, the exons of protein-coding genes harbor more than 90% of variants influencing type 2 diabetes and inflammatory bowel disease, making them good candidates for whole-exome studies. In contrast, <10% of the causal variants for schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder are located in protein-coding exons, indicating a more substantial role of regulatory mechanisms in the pathogenesis of these disorders. AVAILABILITY AND IMPLEMENTATION: The software is available at: https://github.com/precimed/mixer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

10.
Transl Psychiatry ; 10(1): 198, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32555152

RESUMO

Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and N-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (n = 422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300-2500 nmol/L). The smoking-independent analysis of N-desmethylclozapine serum concentration and the CLZ-to-N-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as 'smokers' (61%) or 'nonsmokers' (39%), a novel variant (rs28379954; minor T>C allele frequency 4.1%; 7.6% CT carriers in the population) within the gene encoding the nuclear factor 1 B-type (NFIB) was significantly associated with reduced CLZ serum concentration (p = 1.68 × 10-8, beta = -0.376; explained variance 7.63%). There was no significant association between rs28379954 and N-desmethylclozapine concentration in the GWAS analysis (p = 5.63 × 10-5). The fraction of CLZ TDM samples below 300 nmol/L was significantly higher in carriers vs. noncarriers of the rs28379954 minor C allele [12.0% (95% CI: 9.4-14.7) vs. 6.2% (95% CI: 5.7-6.8), p < 0.001]. We identified a novel variant in the NFIB gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.

11.
Sci Rep ; 10(1): 9101, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499510

RESUMO

Alpha defensins are anti-microbial peptides of the innate immune system. The defensin A1 and A3 genes are located in a repeat array of variable copy number (the DEFA1A3 locus) and encode the human neutrophil peptides 1, 2 and 3. The possibility that copy number variation (CNV) may be associated with infection susceptibility and autoimmune pathology motivated the study of DEFA1A3 CNV across populations. We enhanced two existing methods (one qPCR-based and one sequencing-based) to enable copy number estimation that discriminates between DEFA1 and DEFA3 genes. We used these methods to quantify A1/A3 copy number variation in 2504 samples from the 1000 Genomes high-coverage dataset as well as performing FiberFISH assays on selected samples to visualize the haplotypes. These methods produce accurate estimates and show that there are substantial differences between populations. The African population is a clear outlier with a high frequency of the ancestral pure DEFA1 haplotype, but also harbours exceptionally long haplotypes of 24 copies of both DEFA1 and DEFA3, whilst the East Asian population displays the highest mean level of DEFA3 copy number. Further, our findings demonstrate that qPCR can be an accurate method for CNV estimation and that defensins substantially extend the known range of copy number variation for a human protein-coding gene.

12.
Schizophr Res ; 218: 55-62, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32171635

RESUMO

BACKGROUND: One third of people diagnosed with schizophrenia fail to respond adequately to antipsychotic medication, resulting in persisting disabling symptoms, higher rates of hospitalization and higher costs for society. In an effort to better understand the mechanisms behind resistance to antipsychotic treatment in schizophrenia, we investigated its potential relationship to the genetic architecture of the disorder. METHODS: Patients diagnosed with a schizophrenia spectrum disorder (N = 321) were classified as either being treatment-resistant (N = 108) or non-treatment-resistant (N = 213) to antipsychotic medication using defined consensus criteria. A schizophrenia polygenic risk score based on genome-wide association studies (GWAS) was calculated for each patient and binary logistic regression was performed to investigate the association between polygenetic risk and treatment resistance. We adjusted for principal components, batch number, age and sex. Additional analyses were performed to investigate associations with demographic and clinical variables. RESULTS: High levels of polygenic risk score for schizophrenia significantly predicted treatment resistance (p = 0.003). The positive predictive value of the model was 61.5% and the negative predictive value was 71.7%. The association was significant for one (p = 0.01) out of five tested SNP significance thresholds. Season of birth was able to predict treatment-resistance in the regression model (p = 0.05). CONCLUSIONS: The study indicates that treatment-resistance to antipsychotic medication is associated with higher polygenetic risk of schizophrenia, suggesting a link between antipsychotics mechanism of action and the genetic underpinnings of the disorder.

13.
Biol Psychiatry ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32201043

RESUMO

BACKGROUND: Parkinson's disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders. METHODS: We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci. RESULTS: We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type-specific expression profiles. CONCLUSIONS: Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.

14.
Brain Behav Immun ; 87: 634-644, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32109548

RESUMO

Schizophrenia (SCZ) is a severe mental disorder with a high heritability. Although its pathophysiology is mainly unknown, dysregulated immune activation and inflammation have recently emerged as possible candidates in the underlying mechanisms of SCZ. Previous studies suggest that aberrant inflammasome activation, glia dysregulation, and brain inflammation may be involved in the pathophysiology of the disorder. Here, we studied the effects of inflammatory modulation on human induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Inflammasome activation was mimicked by short-term IL-1ß exposure, and gene expression were measured with high-coverage RNA-Seq to ensure a global characterization of the transcriptional effects of the treatment. IL-1ß exposure modulated several pathways involved in innate immune responses, cell cycle regulation, and metabolism in both SCZ and CTRL astrocytes. Significant differences were found in the expression of HILPDA and CCL20 genes, both of which had reduced up-regulation upon IL-1ß treatment in SCZ astrocytes compared to CTRL astrocytes. CCL20 data were further validated and confirmed using qPCR, ELISA, and regulatory T lymphocyte (Treg) migration assays. Additionally, we found significantly decreased mRNA expression of the Treg-specific marker FOXP3 in the blood of a large cohort of SCZ patients (n = 484) compared to CTRL (n = 472). Since CCL20 is a specific chemoattractant for CD4+CD25+CCR6+ Tregs, which are crucially involved in anti-inflammatory responses during brain (auto)inflammation, our results imply a plausible role for an altered astroglia-CCL20-CCR6-Treg axis in SCZ pathophysiology.

16.
Mol Psychiatry ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047264

RESUMO

Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

17.
Biol Psychiatry ; 87(12): 1052-1062, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061372

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is consistently associated with lower levels of educational attainment. A recent large genome-wide association study identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown. METHODS: We analyzed independent genome-wide association study summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment (N = 842,499), and general intelligence (N = 269,867) using a conditional/conjunctional false discovery rate (FDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations. The genetic variants identified were characterized in terms of function, expression, and biological processes. RESULTS: We identified 58 linkage disequilibrium-independent ADHD-associated loci (conditional FDR < 0.01), of which 30 were shared between ADHD and educational attainment or general intelligence (conjunctional FDR < 0.01) and 46 were novel risk loci for ADHD. CONCLUSIONS: These results expand on previous genetic and epidemiological studies and support the hypothesis of a shared genetic basis between these phenotypes. Although the clinical utility of the identified loci remains to be determined, they can be used as resources to guide future studies aiming to disentangle the complex etiologies of ADHD, educational attainment, and general intelligence.

18.
JAMA Psychiatry ; 77(5): 503-512, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913414

RESUMO

Importance: People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown. Objective: To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them. Design, Setting, and Participants: Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018. Main Outcomes and Measures: The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways. Results: Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways. Conclusions and Relevance: In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

19.
Mol Psychiatry ; 25(11): 3053-3065, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30279459

RESUMO

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

20.
Psychol Med ; 50(4): 595-606, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867076

RESUMO

BACKGROUND: We aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls. METHODS: Patients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples. RESULTS: Significantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10-5), vanillylmandelic acid (VMA, p = 4.5×10-5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10-5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals. CONCLUSIONS: Although prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.

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