RESUMO
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
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
In a follow-up study the results of four arthrodeses, twenty allo-arthroplasties and ten resection-arthroplasties of the shoulder joint are reported. Arthrodeses were done after severe posttraumatic arthrosis or after injuries to the brachial plexus. Allo-arthroplasties resection-arthroplasties were predominantly applied in cases of compound fractures or in tumours. Such operations were indicated rarely and only in cases where the shoulder joint could not be preserved. After allo-arthropaties a high rate of complications was seen. The use of this method should be restricted in cases of tumour; it is only exceptionally indicated in fractures. The resection-arthroplasties showed good or moderate results, if the insertions of the muscles could be preserved.
