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1.
JAMA Psychiatry ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553412

RESUMO

Importance: Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance. Objectives: To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences. Design, Setting and Participants: Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses. Main Outcomes and Measures: Genetic associations with psychotic experience phenotypes. Results: The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10-4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10-3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10-8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10-8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism-based heritability estimate (h2 = 1.71%; 95% CI, 1.02%-2.40%). Conclusions and Relevance: A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders.

2.
Nat Genet ; 51(9): 1339-1348, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31427789

RESUMO

After a decade of genome-wide association studies (GWASs), fundamental questions in human genetics, such as the extent of pleiotropy across the genome and variation in genetic architecture across traits, are still unanswered. The current availability of hundreds of GWASs provides a unique opportunity to address these questions. We systematically analyzed 4,155 publicly available GWASs. For a subset of well-powered GWASs on 558 traits, we provide an extensive overview of pleiotropy and genetic architecture. We show that trait-associated loci cover more than half of the genome, and 90% of these overlap with loci from multiple traits. We find that potential causal variants are enriched in coding and flanking regions, as well as in regulatory elements, and show variation in polygenicity and discoverability of traits. Our results provide insights into how genetic variation contributes to trait variation. All GWAS results can be queried and visualized at the GWAS ATLAS resource ( https://atlas.ctglab.nl ).

4.
Nat Commun ; 10(1): 3222, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324783

RESUMO

Single-cell RNA sequencing (scRNA-seq) data allows to create cell type specific transcriptome profiles. Such profiles can be aligned with genome-wide association studies (GWASs) to implicate cell type specificity of the traits. Current methods typically rely only on a small subset of available scRNA-seq datasets, and integrating multiple datasets is hampered by complex batch effects. Here we collated 43 publicly available scRNA-seq datasets. We propose a 3-step workflow with conditional analyses within and between datasets, circumventing batch effects, to uncover associations of traits with cell types. Applying this method to 26 traits, we identify independent associations of multiple cell types. These results lead to starting points for follow-up functional studies aimed at gaining a mechanistic understanding of these traits. The proposed framework as well as the curated scRNA-seq datasets are made available via an online platform, FUMA, to facilitate rapid evaluation of cell type specificity by other researchers.

5.
Behav Genet ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346826

RESUMO

Neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable and influenced by many single nucleotide polymorphisms (SNPs). SNPs can be used to calculate individual polygenic risk scores (PRS) for a disorder. We aim to explore the association between the PRS for ADHD, ASD and for Schizophrenia (SCZ), and ADHD and ASD diagnoses in a clinical child and adolescent population. Based on the most recent genome wide association studies of ADHD, ASD and SCZ, PRS of each disorder were calculated for individuals of a clinical child and adolescent target sample (N = 688) and for adult controls (N = 943). We tested with logistic regression analyses for an association with (1) a single diagnosis of ADHD (N = 280), (2) a single diagnosis of ASD (N = 295), and (3) combining the two diagnoses, thus subjects with either ASD, ADHD or both (N = 688). Our results showed a significant association of the ADHD PRS with ADHD status (OR 1.6, P = 1.39 × 10-07) and with the combined ADHD/ASD status (OR 1.36, P = 1.211 × 10-05), but not with ASD status (OR 1.14, P = 1). No associations for the ASD and SCZ PRS were observed. In sum, the PRS of ADHD is significantly associated with the combined ADHD/ASD status. Yet, this association is primarily driven by ADHD status, suggesting disorder specific genetic effects of the ADHD PRS.

6.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

7.
Mol Psychiatry ; 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142819

RESUMO

An enigma in studies of neuropsychiatric disorders is how to translate polygenic risk into disease biology. For schizophrenia, where > 145 significant GWAS loci have been identified and only a few genes directly implicated, addressing this issue is a particular challenge. We used a combined cellomics and proteomics approach to show that polygenic risk can be disentangled by searching for shared neuronal morphology and cellular pathway phenotypes of candidate schizophrenia risk genes. We first performed an automated high-content cellular screen to characterize neuronal morphology phenotypes of 41 candidate schizophrenia risk genes. The transcription factors Tcf4 and Tbr1 and the RNA topoisomerase Top3b shared a neuronal phenotype marked by an early and progressive reduction in synapse numbers upon knockdown in mouse primary neuronal cultures. Proteomics analysis subsequently showed that these three genes converge onto the syntaxin-mediated neurotransmitter release pathway, which was previously implicated in schizophrenia, but for which genetic evidence was weak. We show that dysregulation of multiple proteins in this pathway may be due to the combined effects of schizophrenia risk genes Tcf4, Tbr1, and Top3b. Together, our data provide new biological functions for schizophrenia risk genes and support the idea that polygenic risk is the result of multiple small impacts on common neuronal signaling pathways.

8.
Nat Genet ; 51(3): 394-403, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804565

RESUMO

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.


Assuntos
Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Distúrbios do Início e da Manutenção do Sono/genética , Cromatina/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sono/genética
9.
J Am Acad Child Adolesc Psychiatry ; 58(6): 600-607, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30768412

RESUMO

OBJECTIVE: This study examined the relation between polygenic scores (PGSs) for 5 major psychiatric disorders and 2 cognitive traits with brain magnetic resonance imaging morphologic measurements in a large population-based sample of children. In addition, this study tested for differences in brain morphology-mediated associations between PGSs for psychiatric disorders and PGSs for related behavioral phenotypes. METHOD: Participants included 1,139 children from the Generation R Study assessed at 10 years of age with genotype and neuroimaging data available. PGSs were calculated for schizophrenia, bipolar disorder, major depression disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, intelligence, and educational attainment using results from the most recent genome-wide association studies. Image processing was performed using FreeSurfer to extract cortical and subcortical brain volumes. RESULTS: Greater genetic susceptibility for ADHD was associated with smaller caudate volume (strongest prior = 0.01: ß = -0.07, p = .006). In boys, mediation analysis estimates showed that 11% of the association between the PGS for ADHD and the PGS attention problems was mediated by differences in caudate volume (n = 535), whereas mediation was not significant in girls or the entire sample. PGSs for educational attainment and intelligence showed positive associations with total brain volume (strongest prior = 0.5: ß = 0.14, p = 7.12 × 10-8; and ß = 0.12, p = 6.87 × 10-7, respectively). CONCLUSION: The present findings indicate that the neurobiological manifestation of polygenic susceptibility for ADHD, educational attainment, and intelligence involve early morphologic differences in caudate and total brain volumes in childhood. Furthermore, the genetic risk for ADHD might influence attention problems through the caudate nucleus in boys.

10.
Mol Psychiatry ; 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610197

RESUMO

Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders associated with cognitive impairment, which is considered a major determinant of functional outcome. Despite this, the etiology of the cognitive impairment is poorly understood, and no satisfactory cognitive treatments exist. Increasing evidence indicates that genetic risk for SCZ may contribute to cognitive impairment, whereas the genetic relationship between BD and cognitive function remains unclear. Here, we combined large genome-wide association study data on SCZ (n = 82,315), BD (n = 51,710), and general intelligence (n = 269,867) to investigate overlap in common genetic variants using conditional false discovery rate (condFDR) analysis. We observed substantial genetic enrichment in both SCZ and BD conditional on associations with intelligence indicating polygenic overlap. Using condFDR analysis, we leveraged this enrichment to increase statistical power and identified 75 distinct genomic loci associated with both SCZ and intelligence, and 12 loci associated with both BD and intelligence at conjunctional FDR < 0.01. Among these loci, 20 are novel for SCZ, and four are novel for BD. Most SCZ risk alleles (61 of 75, 81%) were associated with poorer cognitive performance, whereas most BD risk alleles (9 of 12, 75%) were associated with better cognitive performance. A gene set analysis of the loci shared between SCZ and intelligence implicated biological processes related to neurodevelopment, synaptic integrity, and neurotransmission; the same analysis for BD was underpowered. Altogether, the study demonstrates that both SCZ and BD share genetic influences with intelligence, albeit in a different manner, providing new insights into their genetic architectures.

11.
Sci Rep ; 8(1): 18060, 2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30575754

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

12.
Science ; 362(6420)2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30545854

RESUMO

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Neurogênese/genética , Encéfalo/crescimento & desenvolvimento , Epigênese Genética , Epigenômica , Redes Reguladoras de Genes , Humanos , Análise de Célula Única , Transcriptoma
13.
Acta Neuropathol ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413934

RESUMO

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

14.
Stem Cell Rev ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30421281

RESUMO

Generation of proper controls is crucial in induced pluripotent stem cell (iPSC) studies. X-chromosomal disorders offer the potential to develop isogenic controls due to random X-chromosomal inactivation (XCI). However, the generation of such lines is currently hampered by skewed X-inactivation in fibroblast lines and X-chromosomal reactivation (XCR) after reprogramming. Here we describe a method to generate a pure iPSC population with respect to the specific inactivated X-chromosome (Xi). We used fibroblasts from Rett patients, who all have a causal mutation in the X-linked MeCP2 gene. Pre-sorting these fibroblasts followed by episomal reprogramming, allowed us to overcome skewness in fibroblast lines and to retain the X-chromosomal state, which was unpredictable with lentiviral reprogramming. This means that fibroblast pre-sorting followed by episomal reprogramming can be used to reliably generate iPSC lines with specified X-chromosomal phenotype such as Rett syndrome.

15.
BJPsych Open ; 4(6): 467-470, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30450226

RESUMO

Prior evolutionary theory provided reason to suspect that measures of development and reproduction would be correlated with antisocial behaviours in human and non-human species. Behavioural genetics has revealed that most quantitative traits are heritable, suggesting that these phenotypic correlations may share genetic aetiologies. We use genome-wide association study data to estimate the genetic correlations between various measures of reproductive development (N = 52 776-318 863) and antisocial behaviour (N = 31 968). Our genetic correlation analyses demonstrate that alleles associated with higher reproductive output (number of children ever born, r g = 0.50, P = 0.0065) were positively correlated with alleles associated with antisocial behaviour, whereas alleles associated with more delayed reproductive onset (age at first birth, r g = -0.64, P = 0.0008) were negatively associated with alleles linked to antisocial behaviour. Ultimately, these findings coalesce with evolutionary theories suggesting that increased antisocial behaviours may partly represent a faster life history approach, which may be significantly calibrated by genes. Declaration of interest: None.

16.
Nutrients ; 10(11)2018 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-30373230

RESUMO

Cow's milk allergy (CMA) is an early-onset allergy of which the underlying genetic factors remain largely undiscovered. CMA has been found to co-occur with other allergies and immunological hypersensitivity disorders, suggesting a shared genetic etiology. We aimed to (1) investigate and (2) validate whether CMA children carry a higher genetic susceptibility for other immunological hypersensitivity disorders using polygenic risk score analysis (PRS) and prospective phenotypic data. Twenty-two CMA patients of the Dutch EuroPrevall birth cohort study and 307 reference subjects were genotyped using single nucleotide polymorphism (SNP) array. Differentially genetic susceptibility was estimated using PRS, based on multiple P-value thresholds for SNP inclusion of previously reported genome-wide association studies (GWAS) on asthma, autism spectrum disorder, atopic dermatitis, inflammatory bowel disease and rheumatoid arthritis. These associations were validated with prospective data outcomes during a six-year follow-up in 19 patients. We observed robust and significantly higher PRSs of asthma in CMA children compared to the reference set. Association analyses using the prospective data indicated significant higher PRSs in former CMA patients suffering from asthma and related traits. Our results suggest a shared genetic etiology between CMA and asthma and a considerable predictive sensitivity potential for subsequent onset of asthma which indicates a potential use for early clinical asthma intervention programs.

17.
Nat Commun ; 9(1): 3768, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30218068

RESUMO

Gene-set analysis provides insight into which functional and biological properties of genes are aetiologically relevant for a particular phenotype. But genes have multiple properties, and these properties are often correlated across genes. This can cause confounding in a gene-set analysis, because one property may be statistically associated even if biologically irrelevant to the phenotype, by being correlated with gene properties that are relevant. To address this issue we present a novel conditional and interaction gene-set analysis approach, which attains considerable functional refinement of its conclusions compared to traditional gene-set analysis. We applied our approach to blood pressure phenotypes in the UK Biobank data (N = 360,243), the results of which we report here. We confirm and further refine several associations with multiple processes involved in heart and blood vessel formation but also identify novel interactions, among others with cardiovascular tissues involved in regulatory pathways of blood pressure homoeostasis.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30243642

RESUMO

BACKGROUND: Genome-wide association studies have identified numerous genetic variants that predispose to neuropsychiatric traits. Identification of mechanisms in the brain that underlie these associations is essential for understanding manifestations of genetic predisposition within the general population. Here, we investigated the association between polygenic scores (PGSs) for seven neuropsychiatric traits and white matter microstructure of the brain on diffusion tensor imaging in the pediatric population. METHODS: Participants from the Generation R Study who had genotype and diffusion tensor imaging data available (n = 1138, mean age = 10.2 years, range = 8.7-12.0) were included. PGSs were calculated for five psychiatric disorders (attention-deficit/hyperactivity disorder, bipolar disorder, autism, major depressive disorder, and schizophrenia) and two cognitive traits (intelligence and educational attainment) and were tested for associations with global and tract-specific fractional anisotropy (FA) and mean diffusivity. RESULTS: Significant positive associations with global FA were observed for the PGSs of intelligence (ß = .109, SE = .029, p < .001, ΔR2 = .012) and educational attainment (ß = .118, SE = .029, p < .001, ΔR2 = .014). No significant associations were observed with FA for the PGSs of psychiatric disorders. Tract-specific analysis showed that the PGSs for intelligence and educational attainment were associated with FA of several association and projection fibers of the brain. CONCLUSIONS: Our results show that genetic predisposition for cognition-related traits, but not for psychiatric disorders, is associated with microstructural diffusion measures of white matter tracts at an early age. These results suggest a shared genetic etiology among structural connectivity, intelligence, and educational achievement.

19.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

20.
Nat Genet ; 50(7): 920-927, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29942085

RESUMO

Neuroticism is an important risk factor for psychiatric traits, including depression1, anxiety2,3, and schizophrenia4-6. At the time of analysis, previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci associated to neuroticism10-12. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 × 10-8), medium spiny neurons (P = 4.23 × 10-8), and serotonergic neurons (P = 1.37 × 10-7). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 × 10-9), behavioral response to cocaine processes (P = 1.84 × 10-7), and axon part (P = 5.26 × 10-8). We show that neuroticism's genetic signal partly originates in two genetically distinguishable subclusters13 ('depressed affect' and 'worry'), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.

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