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The X‐chromosomal MECP2/Mecp2 gene encodes methyl‐CpG‐binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype‐based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele‐specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain‐expressed, species‐conserved miR‐511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 over expression, the human data convey means by which genetic variation affects MECP2 expression and behavior. Synopsis The transcriptional regulator MECP2 is known to affect neurodevelopment. This study associates aggressive social behavior with MECP2 genotype and expression changes in both male schizophrenic patients and mouse models of different genetic background. Mild (50%) overexpression of Mecp2 in mice influences male social aggression. The genetic background (FVB/N versus C57Bl/6N) modulates this overexpression‐associated phenotype. Normal genetic variation of MECP2 (single nucleotide polymorphisms) co‐determines the level of aggression in two independent cohorts of schizophrenic men. miR‐511 downregulates MECP2 expression in T but not C carriers of SNP rs2734647, suggesting miR‐511 targeted therapies in MECP2 gene duplication syndrome. Graphical Abstract The transcriptional regulator MECP2 is known to affect neurodevelopment. This study associates aggressive social behavior with MECP2 genotype and expression changes in both male schizophrenic patients and mouse models of different genetic background.

Background Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia. Methods For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected. Results The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail. Conclusions The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.

The X‐chromosomal MECP2/Mecp2 gene encodes methyl‐CpG‐binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype‐based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele‐specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain‐expressed, species‐conserved miR‐511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 over expression, the human data convey means by which genetic variation affects MECP2 expression and behavior. image The transcriptional regulator MECP 2 is known to affect neurodevelopment. This study associates aggressive social behavior with MECP 2 genotype and expression changes in both male schizophrenic patients and mouse models of different genetic background. Mild (50%) overexpression of Mecp2 in mice influences male social aggression. The genetic background ( FVB /N versus C57Bl/6N) modulates this overexpression‐associated phenotype. Normal genetic variation of MECP 2 (single nucleotide polymorphisms) co‐determines the level of aggression in two independent cohorts of schizophrenic men. miR‐511 downregulates MECP 2 expression in T but not C carriers of SNP rs2734647, suggesting miR‐511 targeted therapies in MECP 2 gene duplication syndrome.