RESUMO
Major depressive disorders (MDDs) and anxiety and stress-related disorders (ASRDs) have overlapping symptoms and high rates of comorbidity. However, the underlying mechanisms remain largely unknown. Here, we aimed to examine whether MDD and ASRD share genetic risk factors utilizing recent large-scale genome-wide association studies (GWASs). To examine the genetic overlap between MDD and ASRD, we applied genetic correlation analysis to analyze GWAS summary statistics for MDD (16,823 cases and 25,632 controls) and ASRD (12,665 cases and 19,225 controls). We found positive and significant genetic correlations between MDD and ASRD (GNOVA: rho = 0.59, se = 0.01, P = 5.32 × 10-45). Our latent causal variable (LCV) analysis indicated the genetic correlation result from pleiotropic effects (gcp = -0.56, se = 0.31, Pgcp = 0.1). Based on pleiotropic enrichment, we performed a cross-trait meta-analysis of MDD and ASRD GWAS and fine-mapped the identified loci. In total, we identified 5 pleiotropic loci simultaneously associated with MDD and ASRD at P < 5 × 10-8. At the gene level, we further demonstrated that MDD- and ASRD-inferred gene expression overlapped across 48 tissues and highlighted the NUP210L gene as a potential mediator of the genetic correlation. Our study highlights a shared underlying genetic risk for MDD and ASRD, which may help to improve the understanding of high comorbidity and overlapping genetic mechanisms between the two traits.
Assuntos
Transtornos de Ansiedade/genética , Comorbidade , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Estresse Psicológico/genética , Feminino , Expressão Gênica , Pleiotropia Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Previous genetic and biological evidence converge on the involvement of synaptic dysfunction in schizophrenia, and OPCML, encoding a synaptic membrane protein, is reported to be genetically associated with schizophrenia. However, its role in the pathophysiology of schizophrenia remains largely unknown. Here, we found that Opcml is strongly expressed in the mouse hippocampus; ablation of Opcml leads to reduced phosphorylated cofilin and dysregulated F-actin dynamics, which disturbs the spine maturation. Furthermore, Opcml interacts with EphB2 to control the stability of spines by regulating the ephrin-EphB2-cofilin signaling pathway. Opcml-deficient mice display impaired cognitive behaviors and abnormal sensorimotor gating, which are similar to features in neuropsychiatric disorders such as schizophrenia. Notably, the administration of aripiprazole partially restores the abnormal behaviors in Opcml-/- mice by increasing the phosphorylated cofilin level and facilitating spine maturation. We demonstrated a critical role of the schizophrenia-susceptible gene OPCML in spine maturation and cognitive behaviors via regulating the ephrin-EphB2-cofilin signaling pathway, providing further insights into the characteristics of schizophrenia.
Assuntos
Fatores de Despolimerização de Actina/genética , Moléculas de Adesão Celular/genética , Cognição/fisiologia , Espinhas Dendríticas/genética , Efrinas/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Animais , Estudos de Casos e Controles , Linhagem Celular , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Espinhas Dendríticas/fisiologia , Feminino , Proteínas Ligadas por GPI/genética , Células HEK293 , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Fosforilação/fisiologia , Esquizofrenia/fisiopatologia , Transdução de Sinais/genéticaRESUMO
Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.