RESUMO
The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1, and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the É4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10-8), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10-8), and rs1513625 near PDCL3 (P-value=4.28 × 10-8). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10-7) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10-7; rs62400067, P-value=3.54 × 10-7). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.
Assuntos
Doença de Alzheimer/genética , Proteínas de Transporte/genética , Proteínas do Tecido Nervoso/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Receptores de Esteroides/genética , Idade de Início , Idoso , Alelos , Apolipoproteínas E/genética , Proteínas de Transporte/metabolismo , Família , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Receptores de Esteroides/metabolismo , Fatores de Risco , tRNA Metiltransferases/genética , tRNA Metiltransferases/metabolismoRESUMO
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
Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.
Assuntos
Transtorno Obsessivo-Compulsivo/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Autorrelato , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do TratamentoRESUMO
Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.
Assuntos
Saúde da Família , Predisposição Genética para Doença/genética , Transtorno Obsessivo-Compulsivo/genética , Adulto , Cromossomos Humanos Par 9/genética , Comportamento Cooperativo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Adulto JovemRESUMO
Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.
Assuntos
Doença de Alzheimer/genética , Variações do Número de Cópias de DNA , Adulto , Idade de Início , Idoso , Estudos de Coortes , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , LinhagemRESUMO
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
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
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).
Assuntos
Transtorno Bipolar/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 16/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Europa (Continente) , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Adulto JovemRESUMO
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
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
Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.
Assuntos
Cromossomos Humanos Par 11/genética , Neuroimagem Funcional/psicologia , Predisposição Genética para Doença/genética , Desempenho Psicomotor/fisiologia , Esquizofrenia/genética , Psicologia do Esquizofrênico , População Branca/genética , Estudos de Casos e Controles , Europa (Continente) , Feminino , Neuroimagem Funcional/métodos , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Giro do Cíngulo/fisiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Esquizofrenia/fisiopatologiaRESUMO
A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
Assuntos
Transtornos de Ansiedade/genética , Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Fatores de Transcrição Kruppel-Like/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Valores de ReferênciaRESUMO
BACKGROUND: Isolated nail dysplasia is rare and has been reported in only a small number of families. OBJECTIVES: To describe and characterize two Pakistani families with an autosomal-recessive inherited nail dysplasia. METHODS: Genome-wide linkage analysis; mutation screening of candidate genes by Sanger sequencing; cloning of FZD6 and protein analyses; immunohistochemistry. RESULTS: We mapped this genodermatosis to chromosome 8q22.3, and identified a homozygous nonsense mutation c.1750G>T (p.E584X) in the frizzled 6 (FZD6) gene in all affected individuals. Immunohistochemical analyses in nail sections from healthy individuals revealed strong expression of FZD6 in the ventral nail matrix and a less pronounced expression of FZD6 in the nail bed. CONCLUSIONS: FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/ß-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic nail disorders anonychia and nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated nail dysplasia. The present results emphasize the important role of the Wnt pathways in nail development and increase understanding of Wnt-mediated developmental events in general.
Assuntos
Cromossomos Humanos Par 8/genética , Códon sem Sentido/genética , Receptores Frizzled/genética , Doenças da Unha/genética , Receptores Wnt/genética , Adulto , Consanguinidade , Feminino , Humanos , Masculino , Linhagem , Via de Sinalização WntRESUMO
Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 x 10(-4) for SREBF1 (rs11868035, odd ration (OR)=1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 x 10(-5) for SREBF2 (rs1057217, OR=1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Predisposição Genética para Doença , Lipogênese/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Adulto , Estudos de Casos e Controles , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 22/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Lipogênese/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Países Escandinavos e NórdicosRESUMO
Cognitive control represents an essential neuropsychological characteristic that allows for the rapid adaption of a changing environment by constant re-allocation of cognitive resources. This finely tuned mechanism is impaired in psychiatric disorders such as schizophrenia and contributes to cognitive deficits. Neuroimaging has highlighted the contribution of the anterior cingulate cortex (ACC) and prefrontal regions (PFC) on cognitive control and demonstrated the impact of genetic variation, as well as genetic liability for schizophrenia. In this study, we aimed to examine the influence of the functional single-nucleotide polymorphism (SNP) rs6265 of a plasticity-related neurotrophic factor gene, BDNF (Val66Met), on cognitive control. Strong evidence implicates BDNF Val66Met in neural plasticity in humans. Furthermore, several studies suggest that although the variant is not convincingly associated with schizophrenia risk, it seems to be a modifier of the clinical presentation and course of the disease. In order to clarify the underlying mechanisms using functional magnetic resonance imaging (fMRI), we studied the effects of this SNP on ACC and PFC activation, and the connectivity between these regions in a discovery sample of 85 healthy individuals and sought to replicate this effect in an independent sample of 253 individuals. Additionally, we tested the identified imaging phenotype in relation to schizophrenia familial risk in a sample of 58 unaffected first-degree relatives of schizophrenia patients. We found a significant increase in interregional connectivity between ACC and PFC in the risk-associated BDNF 66Met allele carriers. Furthermore, we replicated this effect in an independent sample and demonstrated its independence of structural confounds, as well as task specificity. A similar coupling increase was detectable in individuals with increased familial risk for schizophrenia. Our results show that a key neural circuit for cognitive control is influenced by a plasticity-related genetic variant, which may render this circuit particular susceptible to genetic and environmental risk factors for schizophrenia.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Conectoma , Função Executiva/fisiologia , Giro do Cíngulo/fisiopatologia , Rede Nervosa/fisiopatologia , Plasticidade Neuronal/genética , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/genética , Adulto , Feminino , Predisposição Genética para Doença , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/diagnóstico por imagem , Adulto JovemAssuntos
Transtorno Bipolar/genética , Fenótipo , Receptores de GABA-A/genética , Transtorno Bipolar/fisiopatologia , Bases de Dados Genéticas/estatística & dados numéricos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/genéticaRESUMO
Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.
Assuntos
Transtorno Bipolar/genética , Óxido Nítrico Sintase Tipo I/genética , Fosfoproteínas/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação ao Cálcio/genética , Estudos de Casos e Controles , Dinamarca , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Mutação de Sentido Incorreto , Fosfatidilinositol 3-Quinases/genética , Polimorfismo Genético , Análise de Sequência de DNA , Reino Unido , NucleolinaRESUMO
Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.
Assuntos
Encéfalo/fisiopatologia , Emoções , Memória Episódica , Memória de Curto Prazo , Recompensa , Esquizofrenia/genética , Percepção Social , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Encéfalo/diagnóstico por imagem , Neuroimagem Funcional , Predisposição Genética para Doença , Genótipo , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Herança Multifatorial , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Psicologia do EsquizofrênicoRESUMO
Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.