Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Chronic renal failure and growth hormone: effects on GH-IGF axis and leptin

AIM: To analyze the changes in IGF-1, IGFBP-3, leptin and insulin after replacement doses of recombinant human growth hormone (rhGH) in short prepubertal children with chronic renal failure (CRF). PATIENTS AND METHODS: Eleven children (3F:8M), with mean age of 9.6 years, were treated with rhGH (0.23 mg/Kg weekly for 12 months). Serum leptin, insulin, glucose, IGF-1 and IGFBP-3 were measured before, 6 and 12 months after beginning rhGH treatment. RESULTS: The serum levels of leptin, insulin and glucose did not vary during the treatment; normal leptin and glucose levels and high insulin were observed. There was a significant increment of IGF-1 and IGFBP-3 during the use of rhGH. CONCLUSIONS: The replacement doses of rhGH during 12 months in a selected group of CRF children determined an increment in IGF-1 and IGFBP-3, associated to normal serum leptin and insulin resistance.OBJETIVO: Avaliar as alterações de IGF-1, IGFBP-3, leptina e insulina após o uso de doses de reposição de hormônio de crescimento recombinante humano (rhGH) em crianças baixas pré-púberes com insuficiência renal crônica (IRC). CASUÍSTICA E MÉTODOS: Em 11 crianças (3F:8M), com idade média de 9,6 anos, em uso de rhGH (0,23mg/Kg/semana) por 12 meses, foram dosados (antes, 6 e 12 meses após o início do tratamento com rhGH) leptina, insulina, glicemia, IGF-1 e IGFBP-3. RESULTADOS: As concentrações séricas de leptina, insulina e glicemia não variaram significativamente no decorrer do uso do rhGH, sendo observado o padrão de leptina e glicemia normais, com hiperinsulinemia. Houve aumento significativo da IGF-1 e IGFBP-3 durante o uso do rhGH. CONCLUSÕES: O uso de doses de reposição de rhGH durante 12 meses em um grupo selecionado de crianças com IRC propiciou aumento significativo da concentração sérica de IGF-1 e IGFBP-3, com leptinemia normal e resistência insulínica.96497

Nphs1 gene mutations confirm congenital nephrotic syndrome in four Brazilian cases: a novel mutation is described

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOAutosomal recessive mutations in NPHS1 gene are a common cause of congenital nephrotic syndrome (CNS). The disorder is characterized by massive proteinuria that manifests in utero or in the neonatal period during the first 3 months of life. NPHS1 encodes nephrin, a member of the immunoglobulin family of cell adhesion molecules and the main protein expressed at the renal slit diaphragm. Currently, there are approximately 250 mutations described in NPHS1 gene distributed among all nephrin domains. The main objective of this study was to perform the analysis of NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease. We performed direct sequencing of NPHS1 gene in four children. Each patient was heterozygous for two pathogenic mutations disclosing the molecular cause of the disease in 100% of the cases. We identified six different mutations, consisting of one in-frame deletion, one frameshift, and four missense substitutions. The p.Val736Met mutation that is described here for the first time was considered pathogenic by different mutation predictive algorithms. Regardless of the type of mutation, three patients had a bad outcome and died. Despite the small size of the cohort, this study contributed to the increasing number of deleterious mutations in the NPHS1 gene by describing a new mutation. Also, since we identified NPHS1 pathogenic mutations as the cause of the disease in all cases analyzed, it might be a frequent cause of CNS in South Eastern region of Brazil, although the analysis of a larger sample is required to obtain more indicative epidemiological data.Autosomal recessive mutations inNPHS1geneareacommoncauseofcongenital nephrotic syndrome (CNS). The disorder is characterized by massiveproteinuria that manifestsin uteroor in the neonatal period during thefirst3months of life.NPHS1encodes nephrin, a member of the immunoglobulin fam-ily of cell adhesion molecules and the main protein expressed at the renal slitdiaphragm. Currently, there are approximately 250 mutations described in theNPHS1gene distributed among all nephrin domains. The main objective of thisstudy was to perform the analysis of theNPHS1gene in patients with congenitalnephrotic syndrome in order to determine the molecular cause of the disease.Methods:Direct sequencing ofNPHS1gene in four children was performed.Results:Each patient was heterozygous for twopathogenic mutations disclosingthemolecularcauseofthediseasein100%ofthecases.Weidentified six differ-ent mutations, consisting of one in-framedeletion, one frameshift, and four mis-sense substitutions. The p.Val736Met mutation that is described here for thefirsttime was considered pathogenic by different mutation predictive algorithms.Regardless of the type of mutation, three patients had a bad outcome and diedConclusions:Despite the small size of the cohort, this study contributed to theincreasing number of deleterious mutations in theNPHS1gene by describing anew mutation. Also, since we identifiedNPHS1pathogenic mutations as thecause of the disease in all cases analyzed, it might be a frequent cause of CNSin the South Eastern region of Brazil, although the analysis of a larger sampleis required to obtain more indicative epidemiological data219753757FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2012/51109-0478444/08-7; 141072/201