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1.
PLoS Biol ; 18(10): e3000871, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33090992

RESUMO

Mathematical ability is heritable and related to several genes expressing proteins in the brain. It is unknown, however, which intermediate neural phenotypes could explain how these genes relate to mathematical ability. Here, we examined genetic effects on cerebral cortical volume of 3-6-year-old children without mathematical training to predict mathematical ability in school at 7-9 years of age. To this end, we followed an exploration sample (n = 101) and an independent replication sample (n = 77). We found that ROBO1, a gene known to regulate prenatal growth of cerebral cortical layers, is associated with the volume of the right parietal cortex, a key region for quantity representation. Individual volume differences in this region predicted up to a fifth of the behavioral variance in mathematical ability. Our findings indicate that a fundamental genetic component of the quantity processing system is rooted in the early development of the parietal cortex.

2.
Nat Hum Behav ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989287

RESUMO

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

3.
Transl Psychiatry ; 10(1): 113, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317624

RESUMO

ßB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens before it was detected in various brain regions of the mouse, including the hippocampus and the cerebral cortex. Mutations in the mouse Crybb2 gene lead to alterations of sensorimotor gating measured as prepulse inhibition (PPI) and reduced hippocampal size, combined with an altered number of parvalbumin-positive GABAergic interneurons. Decreased PPI and alterations of parvalbumin-positive interneurons are also endophenotypes that typically occur in schizophrenia. To verify the results found in mice, we genotyped 27 single nucleotide polymorphisms (SNPs) within the CRYBB2 gene and its flanking regions and investigated different schizophrenia typical endophenotypes in a sample of 510 schizophrenia patients and 1322 healthy controls. In the case-control study, no association with schizophrenia was found. However, 3 of the 4 investigated haplotype blocks indicated a decreased CRYBB2 mRNA expression. Two of these blocks were associated with poorer antisaccade task performance and altered working memory-linked functional magnetic resonance imaging signals. For the two haplotypes associated with antisaccade performance, suggestive evidence was found with visual memory and in addition, haplotype block 4 showed a nominally significant association with reduced sensorimotor gating, measured as P50 ratio. These results were not schizophrenia-specific, but could be detected in a combined sample of patients and healthy controls. This is the first study to demonstrate the importance of ßB2-crystallin for antisaccade performance and memory function in humans and therefore provides implications for ßB2-crystallin function in the human brain.

4.
Cerebellum ; 19(3): 348-357, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32157568

RESUMO

Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10-8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10-05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

5.
Schizophr Bull ; 46(2): 336-344, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31206164

RESUMO

BACKGROUND: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. METHODS: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. RESULTS: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

7.
Am J Hum Genet ; 105(2): 334-350, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374203

RESUMO

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.


Assuntos
Transtornos Cognitivos/fisiopatologia , Cognição/fisiologia , Escolaridade , Transtornos do Neurodesenvolvimento/etiologia , Polimorfismo de Nucleotídeo Único , Esquizofrenia/fisiopatologia , Transmissão Sináptica , Adulto , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Neurodesenvolvimento/patologia
8.
J Neural Transm (Vienna) ; 126(6): 777-787, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31098723

RESUMO

Previous research revealed experiences of childhood adversity (CA) to be related to less favorable parenting behavior. It can further be expected that maternal oxytocin receptor (OXTR) genes may influence parenting behavior and moderate relationships between CA and parenting behavior. Moreover, associations between the OXTR gene and plasma oxytocin (OT) have been discussed. The present study investigated main effects of the OXTR gene on parenting behavior and plasma OT of mothers, and moderating effects of the OXTR gene on the relationship between mothers' experiences of CA and parenting behavior. We relied on a sample of 193 mothers and their on average 8-year-old children. Maternal experiences of CA were assessed using a standardized interview. A questionnaire for the assessment of child abuse potential and observations of mother-child interaction were used as indicators of parenting behavior. For mothers, we analyzed three polymorphisms (rs53576, rs1042778, rs2254298) of the OXTR gene and plasma OT. Only the rs53576 was associated with mothers' parenting behavior, specifically with maternal sensitivity. The rs2254298 significantly moderated relations between mothers' experiences of CA and parenting behavior. Significant relations could be found only for mothers who were homozygous for the G allele. The G allele of the rs2254298 was further related to increased plasma OT levels. Our findings underline the importance of considering genetic variation when investigating consequences of CA and developing intervention programs that are adapted to an individual's needs.

9.
Transl Psychiatry ; 9(1): 5, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30664620

RESUMO

Alterations of the 5-HT1A receptor and BDNF have consistently been associated with affective disorders. Two functional single nucleotide polymorphisms (SNPs), rs6295 of the serotonin 1A receptor gene (HTR1A) and rs6265 of brain-derived neurotrophic factor gene (BDNF), may impact transcriptional regulation and expression of the 5-HT1A receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT1A receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. Genotyping was performed for rs6265 and rs6295. Subjects showing a genotype with at least three risk alleles (G of rs6295 or A of rs6265) were compared to control genotypes. Cortical surface binding potential (BPND) was computed for 32 cortical regions of interest (ROI). Mixed model was applied to study main and interaction effects of ROI and genotype. ANOVA was used for post hoc analyses. Individuals with the risk genotypes exhibited an increase in 5-HT1A receptor binding by an average of 17% (mean BPND 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BPND and differences could be demonstrated in 10 ROI post hoc. The combination of disadvantageous allelic expression of rs6295 and rs6265 may result in a 5-HT1A receptor profile comparable to affective disorders as increased 5-HT1A receptor binding is a well published phenotype of depression. Thus, epistasis between BDNF and HTR1A may contribute to the multifactorial risk for affective disorders and our results strongly advocate further research on this genetic signature in affective disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Transtorno Depressivo/genética , Epistasia Genética , Receptor 5-HT1A de Serotonina/metabolismo , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos Transversais , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/metabolismo , Polimorfismo de Nucleotídeo Único , Tomografia por Emissão de Pósitrons , Piridinas/metabolismo , Receptor 5-HT1A de Serotonina/genética
10.
Nat Neurosci ; 21(12): 1656-1669, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30482948

RESUMO

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
11.
Front Neurol ; 9: 591, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30079052

RESUMO

Objective: In order to identify genetic variants associated with vestibular neuritis, a common cause of peripheral vertigo with a potential causative link to the reactivation of herpes simplex type 1 (HSV-1), we conducted a genome-wide association study. Methods: Association was assessed using approximately 8 million variants. 131 patients with vestibular neuritis and 2,609 controls of European ancestry were included. Results: Genome-wide associations with vestibular neuritis were detected in 4 regions containing protein coding genes assignable to two functional groups: virus hypothesis and insulin metabolism. Genes of set 1 are related to viral processes: nuclear receptor subfamily 3 group C member 2 (NR3C2) is a receptor for mineralocorticoids and glucocorticoids and was shown to be a host factor for HSV-1 replication. Ankyrin repeat domain 30A (ANKRD30A) encodes a host factor for human immunodeficiency virus-1 (HIV-1) infection. It shows rapid evolution and is induced by interferon stimulation. Mediator complex 30 (MED30), an important member of the mediator complex, has been shown to be involved in replication of HIV-1, a knockdown leading to impaired viral replication. The second set of genes LIM homeobox transcription factor 1 alpha (LMX1A), solute carrier family 30 member 8 (SLC30A8) is associated with insulin metabolism and resistance, a feature of some patients in whom type 2 diabetes is an accompanying comorbidity of vestibular neuritis. Conclusions: Using a GWAS approach to evaluate the etiology of vestibular neuritis these findings provide another piece of evidence that it may be caused by a viral inflammation.

12.
Psychiatry Res ; 270: 992-1000, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30057257

RESUMO

Previously, we reported that Toxoplasma gondii (T. gondii)-seropositivity is associated with higher impulsive sensation seeking in younger men. As dopaminergic and serotonergic signaling regulate impulsivity, and as T. gondii directly and indirectly affects dopaminergic signaling and induces activation of the kynurenine pathway leading to the diversion of tryptophan from serotonin production, we investigated if dopamine and serotonin precursors or the tryptophan metabolite kynurenine interact with the T. gondii-impulsivity association. In 950 psychiatrically healthy participants, trait impulsivity scores were related to T. gondii IgG seropositivity. Interactions were also identified between categorized levels of phenylalanine (Phe), tyrosine (Tyr), Phe:Tyr ratio, kynurenine (Kyn), tryptophan (Trp) and Kyn:Trp ratio, and age and gender. Only younger T. gondii-positive men with a high Phe:Tyr ratio, were found to have significantly higher impulsivity scores. There were no significant associations in other demographic groups, including women and older men. No significant effects or interactions were identified for Phe, Tyr, Kyn, Trp, or Kyn:Trp ratio. Phe:Tyr ratio, therefore, may play a moderating role in the association between T. gondii seropositivity and impulsivity in younger men. These results could potentially lead to individualized approaches to reduce impulsivity, based on combined demographic, biochemical and serological factors.


Assuntos
Anticorpos Antiprotozoários/imunologia , Comportamento Impulsivo , Fenilalanina/metabolismo , Toxoplasma/imunologia , Toxoplasmose/imunologia , Tirosina/metabolismo , Adulto , Fatores Etários , Idoso , Cromatografia Líquida de Alta Pressão , Dopamina/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Alemanha/epidemiologia , Voluntários Saudáveis , Humanos , Imunoglobulina G/imunologia , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Testes Sorológicos , Fatores Sexuais , Toxoplasma/metabolismo , Toxoplasmose/epidemiologia , Toxoplasmose/psicologia , Triptofano/metabolismo
13.
Schizophr Res ; 195: 306-317, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28982554

RESUMO

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.


Assuntos
Transtornos Cognitivos/etiologia , Predisposição Genética para Doença/genética , Imagem por Ressonância Magnética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Transtornos Cognitivos/diagnóstico por imagem , Endofenótipos , Feminino , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Estatísticas não Paramétricas , Adulto Jovem
14.
World J Biol Psychiatry ; 19(8): 602-609, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-28922980

RESUMO

OBJECTIVES: Disturbances in the gamma-frequency band of electroencephalography (EEG) measures are among the most consistently observed intermediate phenotypes in schizophrenia. We assessed whether genetic variations are associated with gamma-band activity. METHODS: We performed a genome-wide association analysis of the early auditory evoked gamma-band response in schizophrenia affected subjects and healthy control individuals (in total N = 315). RESULTS: No marker surpassed the threshold for genome-wide significant association. Several of the markers that were closest to significance mapped to genes involved in neuronal development and the Neuregulin-ErbB signalling network, such as NRG2 and KALRN. Using a gene-set enrichment analysis, we found suggestive evidence for association with genes involved in EEG abnormality (P = .048). CONCLUSIONS: We identified no marker genome-wide significantly associating with gamma response; independent replication of the gene-set analysis result and larger sample sizes will be required to provide leads to cellular pathways involved in gamma-band activity.


Assuntos
Potenciais Evocados Auditivos/fisiologia , Ritmo Gama/fisiologia , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto , Estudos de Casos e Controles , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
J Psychiatr Res ; 91: 98-104, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28327445

RESUMO

Several lines of evidence indicate that suicidal behaviour is partly heritable, with multiple genes implicated in its aetiology. We focused on nine genes (S100A13, EFEMP1, PCDHB5, PDGFRB, CDCA7L, SCN2B, PTPRR, MLC1 and ZFP36) which we previously detected as differentially expressed in the cortex of suicide victims compared to controls. We investigated 84 variants within these genes in 495 suicidal subjects (299 completers and 196 attempters) and 1513 controls (109 post-mortem and 1404 healthy). We evaluated associations with: 1) suicidal phenotype; 2) possible endophenotypes for suicidal behaviour. Overall positive results did not survive the correction threshold. However, we found a nominally different distribution of EFEMP1 genotypes, alleles and haplotypes between suicidal subjects and controls, results that were partially replicated when we separately considered the subgroup of suicide completers and post-mortem controls. A weaker association emerged also for PTPRR. Both EFEMP1 and PTPRR genes were also related to possible endophenotypes for suicidal behaviour such as anger, depression-anxiety and fatigue. Because of the large number of analyses performed and the low significance values further replication are mandatory. Nevertheless, neurotrophic gene variants, in particular EFEMP1 and PTPRR, may have a role in the pathogenesis of suicidal behaviour.


Assuntos
Proteínas da Matriz Extracelular/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Tirosina Fosfatases Classe 7 Semelhantes a Receptores/genética , Comportamento Autodestrutivo/genética , Tentativa de Suicídio/psicologia , Suicídio/psicologia , Adulto , Idoso , Autopsia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Comportamento Autodestrutivo/psicologia , Ideação Suicida , Inquéritos e Questionários
16.
Psychiatry Res ; 249: 212-217, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28119174

RESUMO

Serotonergic neurotransmission dysfunctions have been well documented in patients with suicidal behaviour. We investigated monoamine oxidase A (MAOA: rs2064070, rs6323, rs909525) and B (MAOB: rs1799836, rs2311013, rs2205655) genetic modulation of personality traits (Temperament and Character Inventory, TCI) as endophenotype for suicidal behaviour. 108 suicide attempters and 286 healthy controls of German origin were screened. Among females, allelic analyses revealed associations between MAOA rs6323 A allele and higher Harm Avoidance in suicide attempters and MAOB rs2205655 A allele and higher Cooperativeness scores in healthy controls. Among males, MAOA rs909525 A allele was associated with higher Reward Dependence in suicide attempters. Multivariate analyses controlling for age and educational level mainly confirmed results. Case-control analyses in this subsample do not differ from our previously reported one. Despite of the small sample size, a possible involvement of these genes in the modulation of personality traits closely related to suicidal behaviour cannot be excluded.


Assuntos
Monoaminoxidase/genética , Personalidade/genética , Tentativa de Suicídio/psicologia , Adulto , Alelos , Endofenótipos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Polimorfismo de Nucleotídeo Único
17.
Sci Rep ; 6: 36189, 2016 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-27811963

RESUMO

Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10-4, ß = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10-5, ß = 0.12 s.d., combined P = 2.2 x 10-7, ß = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10-5).


Assuntos
Cognição , Dislexia/genética , Inteligência/genética , Polimorfismo de Nucleotídeo Único , Sucesso Acadêmico , Adolescente , Adulto , Criança , Cromossomos Humanos Par 2/genética , Bases de Dados Genéticas , Escolaridade , Feminino , Marcadores Genéticos , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas Nucleares/genética
18.
Front Public Health ; 4: 182, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27626030

RESUMO

Smoking is highly prevalent in patients with schizophrenia and exerts a negative impact on cardiovascular mortality in these patients. Smoking has complex interactions with monoamine metabolism through the ability of cigarette smoke to suppress Type 1 T helper cell (Th1) type immunity, the immunophenotype that is implicated in phenylalanine hydroxylase (PAH) dysfunction and tryptophan (Trp) breakdown to kynurenine (Kyn) via indoleamine 2,3-dioxygenase. Nicotine also induces tyrosine hydroxylase (TH) gene expression, leading to increased synthesis of catecholamines. Furthermore, there is evidence for PAH dysfunction in schizophrenia. This study aimed to compare the plasma levels of selected monoamine precursors and their metabolites in smokers vs. non-smokers in a large sample of patients with schizophrenia. We measured plasma phenylalanine (Phe), tyrosine (Tyr), Trp, and Kyn levels using high-performance liquid chromatography and calculated Phe:Tyr and Kyn:Trp ratios in 920 patients with schizophrenia. Analysis of variance and linear regression analyses were used to compare these endpoints between three groups of patients with schizophrenia: (1) current smokers, (2) past smokers, and (3) non-smokers. There were significant differences among the three groups with regards to Tyr levels [F (2,789) = 3.77, p = 0.02], with current smokers having lower Tyr levels when compared with non-smokers (p = 0.02). Kyn levels and Kyn:Trp ratio were different among the three groups [F (2,738) = 3.17, p = 0.04, F (2,738) = 3.61, p = 0.03] with current smokers having lower Kyn levels (p = 0.04) and higher Kyn:Trp ratio (p = 0.02) when compared with past smokers. These findings need to be replicated with protocols that include healthy controls to further elucidate the neurobiological underpinnings of altered Tyr and Kyn levels in smokers. Results do suggest potential molecular links between schizophrenia and smoking that may represent biomarkers and treatment targets for reducing an important modifiable cause of general morbidity and mortality in patients with schizophrenia.

19.
Psychosom Med ; 78(8): 931-939, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27359171

RESUMO

OBJECTIVE: Several studies have reported an association between nonceliac gluten sensitivity and schizophrenia. Immune and kynurenine (KYN) pathways have also been implicated in the pathophysiology of schizophrenia, and certain proinflammatory immune mediators may increase KYN and reduce tryptophan (TRP) levels. METHODS: We measured serum antigliadin immunoglobulin G (IgG), KYN, and TRP in 950 patients with schizophrenia. Patients with antibody level at the 90th percentile or higher of control participants (21.9% of all patients) were classified as having elevated antigliadin IgG. Independent t tests and linear regression models were used to compare TRP, KYN, and KYN-TRP ratio (indicator of TRP metabolism) between patients with and those without elevated antigliadin IgG. The correlation between antigliadin IgG and TRP, KYN, and the ratio was also evaluated in the patients. RESULTS: KYN and KYN-TRP ratio were higher in patients with elevated antigliadin IgG (geometric mean [standard deviation {SD}] = 2.65 [0.25] µmol/L versus 2.25 [0.23] µmol/L [p < .001] and 0.05 [0.26] versus 0.04 [0.25; p = .001] respectively), findings robust to adjustment for potential demographic and clinical confounders. Antigliadin IgG positively correlated with KYN and KYN-TRP ratio (r = 0.12, p < .001; r = 0.11, p = .002). TRP did not differ between the two groups and did not correlate with antigliadin IgG. CONCLUSIONS: Our results connect nonceliac gluten sensitivity with the KYN pathway of TRP metabolism in psychotic illness and hint toward potential individualized treatment targets.


Assuntos
Gliadina/imunologia , Imunoglobulina G/sangue , Cinurenina/sangue , Esquizofrenia/sangue , Esquizofrenia/imunologia , Triptofano/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Pteridines ; 27(3-4): 77-85, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28943719

RESUMO

We previously reported that trait aggression, proposed as an endophenotype for suicidal behavior, is positively associated with Toxoplasma gondii (T. gondii) seropositivity in females, but not in males. Additionally, older males seropositive for T. gondii had lower scores on measures of trait aggression, including self-aggression. Trait aggression may be influenced by dopaminergic signaling, which is known to be moderated by gender and age, and potentially enhanced in T. gondii positives through the intrinsic production of dopamine by the microorganism. Therefore, we investigated associations between trait aggression and interactions between T. gondii enzyme-linked immunoabsorbant assay (ELISA) IgG titer-determined seropositivity and high-performance liquid chromatography- (HPLC-) measured blood levels of dopamine precursors phenylalanine (Phe), tyrosine (Tyr), and their ratio in a sample of 1000 psychiatrically healthy participants. Aggressive traits were assessed using the questionnaire for measuring factors of aggression (FAF), the German version of the Buss-Durkee hostility questionnaire. We found that 1) the decrease in trait aggression scores in T. gondii-positive older males was only present in individuals with a low Phe:Tyr ratio, and 2) that there was a positive correlation between Phe:Tyr ratio and total aggression and selected subscales of aggression in T. gondii-positive males, but not in T. gondii-negative males. These findings point toward a gender-specific reciprocal moderation by Phe:Tyr ratio and T. gondii seropositivity of their associations with aggression scores, and lead to experimental interventions geared to manipulating levels of dopamine precursors in selected T. gondii positive individuals with increased propensity for aggression.

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