RESUMO
We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Esquizofrenia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 10 , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Adulto JovemAssuntos
Encéfalo/embriologia , Transtornos Globais do Desenvolvimento Infantil/genética , Montagem e Desmontagem da Cromatina/genética , Exoma/genética , Regulação da Expressão Gênica no Desenvolvimento , Mutação , Transcrição Gênica , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Humanos , Complexos Multiproteicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologiaRESUMO
We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)>2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.
Assuntos
Genoma/fisiologia , Transtornos Neuróticos/genética , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Simulação por Computador , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Feminino , Frequência do Gene , Marcadores Genéticos/genética , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Programas de Rastreamento/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Inventário de PersonalidadeAssuntos
Genética Populacional , Desequilíbrio de Ligação , Animais , Proteína BRCA2 , Estudos de Casos e Controles , Finlândia , Efeito Fundador , Frequência do Gene , Genes BRCA1 , Variação Genética , Humanos , Itália , Judeus/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Recombinação Genética , Projetos de Pesquisa , Fatores de Transcrição/genéticaRESUMO
MicroRNAs orchestrate brain functioning via interaction with microRNA recognition elements (MRE) on target transcripts. However, the global impact of potential competition on the microRNA pool between coding and non-coding brain transcripts that share MREs with them remains unexplored. Here we report that non-coding pseudogene transcripts carrying MREs (PSG+MRE) often show duplicated origin, evolutionary conservation and higher expression in human temporal lobe neurons than comparable duplicated MRE-deficient pseudogenes (PSG-MRE). PSG+MRE participate in neuronal RNA-induced silencing complexes (RISC), indicating functional involvement. Furthermore, downregulation cell culture experiments validated bidirectional co-regulation of PSG+MRE with MRE-sharing coding transcripts, frequently not their mother genes, and with targeted microRNAs; also, PSG+MRE single-nucleotide polymorphisms associated with schizophrenia, bipolar disorder and autism, suggesting interaction with mental diseases. Our findings indicate functional roles of duplicated PSG+MRE in brain development and cognition, supporting physiological impact of the reciprocal co-regulation of PSG+MRE with MRE-sharing coding transcripts in human brain neurons.