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BACKGROUND: Research suggests that Alopecia areata (AA) and Major Depressive Disorder (MDD) show substantial comorbidity. To date, no study has investigated the hypothesis that this is attributable to shared genetic aetiology. OBJECTIVES: To investigate AA-MDD comorbidity on the epidemiological and molecular genetic levels. METHODS: First, epidemiological analyses were performed using data from a cohort of adult German health insurance beneficiaries (n = 1.855 million) to determine the population-based prevalence of AA-MDD comorbidity. Second, analyses were performed to determine the prevalence of MDD in a clinical AA case-control sample with data on psychiatric phenotypes, stratifying for demographic factors to identify possible contributing factors to AA-MDD comorbidity. Third, the genetic overlap between AA and MDD was investigated using a polygenic risk score (PRS) approach and linkage disequilibrium score (LDSC) regression. For PRS, summary statistics from a large MDD GWAS meta-analysis (PGC-MD2) were used as the training sample, while a Central European AA cohort, including the above-mentioned AA patients, and an independent replication US-AA cohort were used as target samples. LDSC was performed using summary statistics of PGC-MD2 and the largest AA meta-analysis to date. RESULTS: High levels of AA-MDD comorbidity were reported in the population-based (MDD in 24% of AA patients), and clinical samples (MDD in 44% of AA patients). MDD-PRS explained a modest proportion of variance in AA case-control status (R2 = 1%). This signal was limited to the major histocompatibility complex (MHC) region on chromosome 6. LDSC regression (excluding MHC) revealed no significant genetic correlation between AA and MDD. CONCLUSIONS: As in previous research, AA patients showed an increased prevalence of MDD. The present analyses suggest that genetic overlap may be confined to the MHC region, which is implicated in immune function. More detailed investigation is required to refine understanding of how the MHC is involved in the development of AA and MDD comorbidity.
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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.
Assuntos
Caderinas/genética , Transtornos do Humor/genética , Adulto , Tonsila do Cerebelo/fisiopatologia , Transtorno Bipolar/genética , Encéfalo/fisiopatologia , Caderinas/metabolismo , Cognição/fisiologia , Dendritos , Espinhas Dendríticas , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal , Neurônios , Personalidade/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sinapses/genética , Sinapses/metabolismoRESUMO
Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-É4 (apolipoprotein E-É4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.
Assuntos
Doença de Alzheimer/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Biomarcadores , Clusterina/genética , Disfunção Cognitiva/genética , Demência/genética , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
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 , Ansiedade/complicações , Transtornos de Ansiedade/genética , Encéfalo/metabolismo , Encéfalo/fisiologia , Estudos de Casos e Controles , Cognição/fisiologia , Medo/fisiologia , Medo/psicologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Masculino , Mutação/genética , Transtorno de Pânico/genética , Receptores de Glicina/metabolismo , Reflexo de Sobressalto/genéticaRESUMO
On a pathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is a decrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e.â¯g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated.
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Angioedema , Inibidores da Enzima Conversora de Angiotensina , Bradicinina , Angioedema/induzido quimicamente , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina/efeitos adversos , Histamina , HumanosRESUMO
Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Dinamarca , Feminino , Predisposição Genética para Doença/genética , Alemanha , Humanos , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
Bipolar disorder (BD) has a multifactorial etiology. Its development is influenced by genetic as well as environmental factors. Large genome-wide association studies (GWAS), in which genetic risk allelic variants for the disorder could be replicated for the first time, marked the breakthrough in the identification of the responsible risk genes. In addition to these common genetic variants with moderate effects identified by GWAS, rare variants with a higher penetrance are expected to play a role in disease development. The results of recent studies suggest that copy number variants might contribute to BD development, although to a lesser extent than in other psychiatric disorders, such as schizophrenia or autism. Results from the initial next generation sequencing studies indicate an enrichment of rare variants in pathways and genes that were previously found to be associated with BD. In the field of pharmacogenetics, a risk gene that influences the individual variance in the response to lithium treatment was identified for the first time in a recent large international GWAS. Currently the reported risk alleles do not sufficiently explain the phenotypic variance to be used for individual prediction of disease risk, disease course or response to medication. Future genetic research will provide important insights into the biological basis of BD by the identification of additional genes associated with BD. This knowledge of genetics will help identify potential etiological subgroups as well as cross-diagnostic disease mechanisms.
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Transtorno Bipolar/genética , Alelos , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Compostos de Lítio/uso terapêutico , FarmacogenéticaRESUMO
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 Hereditários/diagnóstico , Angioedemas Hereditários/genética , Fator XII/genética , Homozigoto , Mutação , Adulto , Idoso , Alelos , Substituição de Aminoácidos , Brasil , Códon , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.
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Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Adulto , Animais , Células COS , Chlorocebus aethiops , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Masculino , Mutação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Esquizofrenia/metabolismoRESUMO
Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fisher's exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus depriving them of its nutritive properties. Furthermore, the present data suggest that fore- and hindgut malformations involve differing environmental factors. Maternal periconceptional multivitamin supplementation was highest among patients with the combined phenotype. This latter finding is contrary to expectation, and warrants further analysis in large prospective epidemiological studies.
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Malformações Anorretais/etiologia , Atresia Esofágica/etiologia , Fístula Traqueoesofágica/etiologia , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Malformações Anorretais/epidemiologia , Peso ao Nascer , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Suplementos Nutricionais/efeitos adversos , Atresia Esofágica/epidemiologia , Feminino , Alemanha/epidemiologia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Mães/estatística & dados numéricos , Fenótipo , Gravidez , Cuidado Pré-Natal/estatística & dados numéricos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Técnicas de Reprodução Assistida/efeitos adversos , Fatores de Risco , Fumar/efeitos adversos , Estatísticas não Paramétricas , Fístula Traqueoesofágica/epidemiologia , Vitaminas/efeitos adversosRESUMO
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.
Assuntos
Substância Cinzenta/fisiopatologia , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto , Análise de Variância , Feminino , Variação Genética , Genótipo , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Lobo Temporal/fisiopatologia , Substância Branca/fisiopatologiaRESUMO
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.
Assuntos
Fatores de Transcrição ARNTL/genética , Caderinas/genética , Infecções por Citomegalovirus/complicações , Interação Gene-Ambiente , Proteínas de Homeodomínio/genética , Esquizofrenia/genética , Nexinas de Classificação/genética , Fatores de Transcrição/genética , alfa Catenina/genética , Estudos de Casos e Controles , Infecções por Citomegalovirus/genética , Dinamarca , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Alemanha , Humanos , Exposição Materna , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/complicações , População Branca/genética , Homeobox 1 de Ligação a E-box em Dedo de ZincoRESUMO
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.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Criança , Planejamento em Saúde Comunitária , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Alelos , Povo Asiático/genética , Encéfalo/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Estudos de Casos e Controles , Cognição , Bases de Dados Genéticas , Regulação para Baixo , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Personalidade/genética , Polimorfismo de Nucleotídeo Único/genética , Mapas de Interação de Proteínas/genética , População Branca/genéticaRESUMO
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.
Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Hipocampo/patologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Biologia Computacional , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fenótipo , RNA Mensageiro/metabolismo , População Branca/genéticaRESUMO
BACKGROUND: Monilethrix is a rare monogenic dystrophic hair loss disorder with high levels of intrafamilial and interfamilial variability. It is characterized by diffuse occipital or temporal alopecia, hair fragility and follicular hyperkeratosis of the occipital region. Mutations in the keratin genes KRT81, KRT83 and KRT86 lead to autosomal dominant monilethrix, whereas mutations in the desmoglein 4 gene (DSG4) cause an autosomal recessive form. AIM: To identify the mutation in a consanguineous Turkish family with three affected children and apparently unaffected parents. METHODS: Sequencing analysis of the genes DSG4 and KRT86 was performed. SNaPshot analysis was conducted to quantify the proportion of cells carrying the KRT86 mutation and to confirm maternal mosaicism of KRT86. RESULTS: No pathogenic mutation was found by sequencing analysis of DSG4; however, analysis of KRT86 revealed a novel mutation, c.1231G>T;p.Glu411*, in exon 7 in the three affected children and their mother. The mutation signal was weaker in the mother than in the three siblings, and SNaPshot analysis revealed substantial mutation-level variation between the children and their mother. CONCLUSIONS: Our results extend the spectrum of KRT86 mutations and indicate KRT86 mosaicism in the family examined. This study is the first, to our knowledge, to describe mosaicism for a monogenic hair loss disorder, and suggests that mosaicism leads to a mild manifestation of monilethrix.
Assuntos
Predisposição Genética para Doença/genética , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Monilétrix/genética , Mosaicismo , Mutação , Adolescente , Povo Asiático , Criança , Desmogleínas/genética , Feminino , Humanos , Masculino , Linhagem , TurquiaRESUMO
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.
Assuntos
Transtorno Bipolar/patologia , Córtex Cerebral/patologia , Proteoglicanas de Sulfatos de Condroitina/genética , Lectinas Tipo C/genética , Imageamento por Ressonância Magnética/métodos , Proteínas do Tecido Nervoso/genética , Esquizofrenia/patologia , Adulto , Transtorno Bipolar/genética , Córtex Cerebral/metabolismo , Genótipo , Humanos , Imageamento por Ressonância Magnética/instrumentação , Neurocam , Lobo Occipital/metabolismo , Lobo Occipital/patologia , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Risco , Esquizofrenia/genéticaRESUMO
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.
Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Predisposição Genética para Doença , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Anquirinas/genética , Anquirinas/metabolismo , Antidepressivos/farmacologia , Povo Asiático/genética , Linhagem Celular Transformada , Citocinas/genética , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Lectinas/genética , Lectinas/metabolismo , Cloreto de Lítio/farmacologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , RNA Mensageiro/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Fatores de Tempo , Ácido Valproico/farmacologia , População Branca/genéticaRESUMO
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.
Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Adulto , Fatores Etários , Idade de Início , Transtorno Bipolar/diagnóstico , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Alemanha/epidemiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
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.