RESUMEN
Misfit strains arising from a film-substrate mismatch can induce novel phases and properties in the epitaxial films of perovskite oxides. Here we employ yet another effect, namely, strain-assisted formation of oxygen vacancies. We demonstrate the misfit-promoted presence of oxygen vacancies and related substitutional incorporation of anion dopants in the epitaxial films of archetypal perovskite oxide SrTiO3. Both the oxygen vacancies and hydrogen or nitrogen dopants are introduced in situ during the pulsed-laser deposition of the films using compressive substrates. The films exhibit peculiar chemical expansion and optical properties, which are consistent with substitutional anion doping.
RESUMEN
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Asunto(s)
Cadherinas/genética , Trastornos del Humor/genética , Adulto , Amígdala del Cerebelo/fisiopatología , Trastorno Bipolar/genética , Encéfalo/fisiopatología , Cadherinas/metabolismo , Cognición/fisiología , Dendritas , Espinas Dendríticas , Trastorno Depresivo Mayor/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Plasticidad Neuronal , Neuronas , Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Sinapsis/genética , Sinapsis/metabolismoRESUMEN
The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.
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Agorafobia/genética , Agorafobia/metabolismo , Receptores de Glicina/genética , Adulto , Alelos , Ansiedad/complicaciones , Trastornos de Ansiedad/genética , Encéfalo/metabolismo , Encéfalo/fisiología , Estudios de Casos y Controles , Cognición/fisiología , Miedo/fisiología , Miedo/psicología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Alemania , Humanos , Masculino , Mutación/genética , Trastorno de Pánico/genética , Receptores de Glicina/metabolismo , Reflejo de Sobresalto/genéticaRESUMEN
Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the C1 inhibitor gene SERPING1. Phenotype and clinical features of the disease are extremely heterogeneous, varying even within the same family. Compared to HAE cohorts in other countries, the genetic background of the Swiss HAE patients has not yet been elucidated. In the present study we investigated the mutational spectrum of the SERPING1 gene in 19 patients of nine unrelated Swiss families. The families comprise a total of 111 HAE-affected subjects which corresponds to approximately 70% of all HAE-affected patients living in Switzerland. Three of the identified mutations are newly described. Members of family A with a nucleotide duplication as genetic background seem to have a more intense disease manifestation with a higher attack frequency compared to the other families. Newly designed genetic screening tests allow a fast and cost-efficient testing for HAE in other family members.
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Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/genética , Proteínas Inactivadoras del Complemento 1/genética , Adulto , Anciano , Proteína Inhibidora del Complemento C1 , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Suiza , Adulto JovenRESUMEN
Hereditary angio-oedema (HAE) with normal C1 inhibitor is associated with heterozygous mutations in the factor XII gene (FXII-HAE). We report two Brazilian FXII-HAE families segregating the mutation c.983 C>A (p.Thr328Lys). In each family, one patient with a homozygous mutation was found. The homozygous female patient in family 1 displayed a severe phenotype. However, this falls within the clinical phenotype spectrum reported for heterozygous female mutation carriers. The homozygous male patient in family 2 also showed a severe phenotype. This finding is intriguing, as to our knowledge, it is the first such report for a male FXII-HAE mutation carrier. In the rare instances in which male mutation carriers are affected, a mild phenotype is typical. The present findings therefore suggest that homozygous FXII-HAE mutation status leads to a severe phenotype in females and males, and to an increased risk of manifest symptoms in the latter.
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Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/genética , Factor XII/genética , Homocigoto , Mutación , Adulto , Anciano , Alelos , Sustitución de Aminoácidos , Brasil , Codón , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.
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Predisposición Genética a la Enfermedad/genética , Predisposición Genética a la Enfermedad/historia , Variación Genética/genética , Esquizofrenia/genética , Estudio de Asociación del Genoma Completo/historia , Estudio de Asociación del Genoma Completo/métodos , Genómica , Genotipo , Historia del Siglo XX , Historia del Siglo XXI , Humanos , PubMed/estadística & datos numéricosRESUMEN
BACKGROUND: The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance. METHODS: In total, 1725 consecutive patients with angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because angioedema was related to a specific factor. RESULTS: According to the new classification of angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired angioedema (AAE; n = 681). The former group included HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE; n = 353) and HAE with normal C1-INH levels (n = 24), of which six had a factor XII mutation (FXII-HAE) and 18 had disease of unknown origin (U-HAE). The AAE group included disease with C1-INH deficiency (C1-INH-AAE; n = 49), AAE related to angiotensin-converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH-AAE; n = 379) and idiopathic nonhistaminergic angioedema (InH-AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII-HAE and U-HAE groups pooled (FXII/U-HAE) versus InH-AAE. The median age at onset of FXII/U-HAE and InH-AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U-HAE and 81% of those with InH-AAE reported more than five attacks per year (median duration of 48 h). The location of angioedema in patients with FXII/U-HAE versus those with InH-AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U-HAE and in 37 of 38 with InH-AAE who were started on this treatment. CONCLUSION: Our findings in this cohort of patients with angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.
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Angioedema/diagnóstico , Angioedemas Hereditarios/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Angioedema/etiología , Angioedema/terapia , Angioedemas Hereditarios/genética , Angioedemas Hereditarios/terapia , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Niño , Proteína Inhibidora del Complemento C1/genética , Factor XII/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. METHOD: We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. RESULTS: We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. CONCLUSIONS: Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.
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Sustancia Gris/fisiopatología , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adulto , Análisis de Varianza , Femenino , Variación Genética , Genotipo , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de Riesgo , Lóbulo Temporal/fisiopatología , Sustancia Blanca/fisiopatologíaRESUMEN
The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P≤0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.
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Trastorno Bipolar/genética , Trastorno Bipolar/metabolismo , Ácido Quinurénico/líquido cefalorraquídeo , Quinurenina 3-Monooxigenasa/biosíntesis , Quinurenina 3-Monooxigenasa/genética , Trastornos Psicóticos/genética , Trastornos Psicóticos/metabolismo , Adulto , Anciano , Alelos , Trastorno Bipolar/complicaciones , Trastorno Bipolar/diagnóstico , Estudios de Casos y Controles , Línea Celular , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad/genética , Hipocampo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal/metabolismo , Trastornos Psicóticos/complicaciones , Esquizofrenia/líquido cefalorraquídeo , Esquizofrenia/metabolismo , Adulto JovenRESUMEN
Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.
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Factores de Transcripción ARNTL/genética , Cadherinas/genética , Infecciones por Citomegalovirus/complicaciones , Interacción Gen-Ambiente , Proteínas de Homeodominio/genética , Esquizofrenia/genética , Nexinas de Clasificación/genética , Factores de Transcripción/genética , alfa Catenina/genética , Estudios de Casos y Controles , Infecciones por Citomegalovirus/genética , Dinamarca , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Alemania , Humanos , Exposición Materna , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/complicaciones , Población Blanca/genética , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Ubiquitina-Proteína Ligasas/genética , Adolescente , Adulto , Anciano , Niño , Planificación en Salud Comunitaria , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
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Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Psicología del Esquizofrénico , Alelos , Pueblo Asiatico/genética , Encéfalo/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Estudios de Casos y Controles , Cognición , Bases de Datos Genéticas , Regulación hacia Abajo , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Mapas de Interacción de Proteínas/genética , Población Blanca/genéticaRESUMEN
Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
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Trastorno Bipolar/etnología , Trastorno Bipolar/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Hipocampo/patología , Polimorfismo de Nucleótido Simple/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Estudios de Casos y Controles , Biología Computacional , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Fenotipo , ARN Mensajero/metabolismo , Población Blanca/genéticaRESUMEN
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1Inh) associated with the c.983C>A and c.983C>G mutations of the F12 gene (FXII-HAE) is a rare condition, and presents with highly variable clinical expression. On the basis of data gathered from a large carrier cohort, we assessed the modifiers affecting the clinical phenotype. METHODS: We analyzed clinical and biological data recorded from 118 mutation carriers (80 symptomatic and 38 asymptomatic), 58 noncarrier relatives from 40 families, and 200 healthy donors. Disease severity was scored in relation to frequency and location of edema, as well as age at disease onset. To predict FXII-HAE disease severity, we analyzed the biological phenotype [C1Inh, C4, spontaneous amidase, angiotensin-I-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N/M (CPN)] by means of logistic regression (Akaike information criterion) and odds ratio (OR). RESULTS: Meaningful variables contributed to FXII-HAE, with the kinin catabolism enzymes ACE and CPN exhibiting a significant inverse relationship with disease severity (OR = 0.36, 95% CI 0.23-0.59, P < 0.001; OR = 0.58, 95% CI 0.36-0.91, P < 0.05, respectively). CPN activities were 37.5 (28.5-41.3) nmol/ml/min and 38.5 (32.8-45.6) for FXII-HAE asymptomatic and symptomatic carriers, respectively, and 37.9 (30.5-43.7) nmol/ml/min for noncarriers. Angiotensin-I-converting enzyme activities were 58 (44-76) and 49 (35-59) nmol/ml/min for FXII-HAE asymptomatic and symptomatic carriers, respectively, and 56 (49-66) nmol/ml/min for noncarriers. CONCLUSIONS: The FXII-HAE is associated with modifiers, for example kinin catabolism enzymes, ACE and CPN, different from those recognized in HAE with C1Inh deficiency.
Asunto(s)
Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/genética , Factor XII/genética , Mutación , Fenotipo , Alelos , Angioedemas Hereditarios/metabolismo , Estudios de Casos y Controles , Proteínas Inactivadoras del Complemento 1/metabolismo , Proteína Inhibidora del Complemento C1 , Exones , Femenino , Heterocigoto , Humanos , Masculino , Oportunidad Relativa , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Recent studies have provided strong evidence that variation in the gene neurocan (NCAN, rs1064395) is a common risk factor for bipolar disorder (BD) and schizophrenia. However, the possible relevance of NCAN variation to disease mechanisms in the human brain has not yet been explored. Thus, to identify a putative pathomechanism, we tested whether the risk allele has an influence on cortical thickness and folding in a well-characterized sample of patients with schizophrenia and healthy controls. METHOD: Sixty-three patients and 65 controls underwent T1-weighted magnetic resonance imaging (MRI) and were genotyped for the single nucleotide polymorphism (SNP) rs1064395. Folding and thickness were analysed on a node-by-node basis using a surface-based approach (FreeSurfer). RESULTS: In patients, NCAN risk status (defined by AA and AG carriers) was found to be associated with higher folding in the right lateral occipital region and at a trend level for the left dorsolateral prefrontal cortex. Controls did not show any association (p > 0.05). For cortical thickness, there was no significant effect in either patients or controls. CONCLUSIONS: This study is the first to describe an effect of the NCAN risk variant on brain structure. Our data show that the NCAN risk allele influences cortical folding in the occipital and prefrontal cortex, which may establish disease susceptibility during neurodevelopment. The findings suggest that NCAN is involved in visual processing and top-down cognitive functioning. Both major cognitive processes are known to be disturbed in schizophrenia. Moreover, our study reveals new evidence for a specific genetic influence on local cortical folding in schizophrenia.
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Trastorno Bipolar/patología , Corteza Cerebral/patología , Proteoglicanos Tipo Condroitín Sulfato/genética , Lectinas Tipo C/genética , Imagen por Resonancia Magnética/métodos , Proteínas del Tejido Nervioso/genética , Esquizofrenia/patología , Adulto , Trastorno Bipolar/genética , Corteza Cerebral/metabolismo , Genotipo , Humanos , Imagen por Resonancia Magnética/instrumentación , Neurocano , Lóbulo Occipital/metabolismo , Lóbulo Occipital/patología , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Riesgo , Esquizofrenia/genéticaRESUMEN
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of â¼750,000 high-quality genetic markers on a combined sample of â¼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of â¼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the â¼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
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Trastorno Bipolar/etnología , Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Metaanálisis como Asunto , Polimorfismo de Nucleótido Simple , Ancirinas/genética , Ancirinas/metabolismo , Antidepresivos/farmacología , Pueblo Asiatico/genética , Línea Celular Transformada , Citocinas/genética , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , Lectinas/genética , Lectinas/metabolismo , Cloruro de Litio/farmacología , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , ARN Mensajero/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Factores de Tiempo , Ácido Valproico/farmacología , Población Blanca/genéticaRESUMEN
We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset < or =21 years (AO < or =21 years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO < or =21 years and AO>21 years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO < or =21 years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO < or = 21 years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO< or = 21 years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.
Asunto(s)
Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Adulto , Factores de Edad , Edad de Inicio , Trastorno Bipolar/diagnóstico , Estudios de Casos y Controles , Bases de Datos Genéticas , Femenino , Estudio de Asociación del Genoma Completo/métodos , Alemania/epidemiología , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.
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Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Proteínas Tirosina Fosfatasas/genética , Proteínas Proto-Oncogénicas/genética , Intento de Suicidio/psicología , Encéfalo/metabolismo , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.
Asunto(s)
Alelos , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno Bipolar/complicaciones , Niño , Femenino , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Población Blanca/genéticaRESUMEN
Schizophrenia is associated with marked deficits in theory of mind (ToM), a higher-order form of social cognition representing the thoughts, emotions and intentions of others. Altered brain activation in the medial prefrontal cortex and temporo-parietal cortex during ToM tasks has been found in patients with schizophrenia, but the relevance of these neuroimaging findings for the heritable risk for schizophrenia is unclear. We tested the hypothesis that activation of the ToM network is altered in healthy risk allele carriers of the single-nucleotide polymorphism rs1344706 in the gene ZNF804A, a recently discovered risk variant for psychosis with genome-wide support. In all, 109 healthy volunteers of both sexes in Hardy-Weinberg equilibrium for rs1344706 were investigated with functional magnetic resonance imaging during a ToM task. As hypothesised, risk carriers exhibited a significant (P<0.05 false discovery rate, corrected for multiple comparisons) risk allele dose effect on neural activity in the medial prefrontal cortex and left temporo-parietal cortex. Moreover, the same effect was found in the left inferior parietal cortex and left inferior frontal cortex, which are part of the human analogue of the mirror neuron system. In addition, in an exploratory analysis (P<0.001 uncorrected), we found evidence for aberrant functional connectivity between the frontal and temporo-parietal regions in risk allele carriers. To conclude, we show that a dysfunction of the ToM network is associated with a genome-wide supported genetic risk variant for schizophrenia and has promise as an intermediate phenotype that can be mined for the development of biological interventions targeted to social dysfunction in psychiatry.