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

Mapping genomic loci prioritises genes and implicates 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

Cytoglobin expression of rectal subepithelial myofibroblasts: Significant alterations of cytoglobin+ stromal cells in long-standing ulcerative colitis

Cytoglobin/stellate cell activation-associated protein (Cygb/STAP), a hemoprotein, functions as part of an O2 reservoir with protective effects against oxidative stress in hepatic stellate cells. Heterogeneous expression of the neural cell adhesion molecule (NCAM)+ and/or α-smooth muscle actin (αSMA)+ has been noted in subepithelial myofibroblasts and interstitial cells of the same lineage in the colorectum. We have demonstrated that early genomic instability of both epithelial and stromal cells in ulcerative colitis (UC) is important for colorectal tumorigenesis, as well as for mucosal remodeling. To further clarify possible roles of stromal cells in mucosal remodeling and tumor development in UC, we here focused on Cygb expression of subepithelial myofibroblasts and interstitial cells, as well as αSMA and HSP47. Noncancerous mucosa of resected rectae from UC patients with or without colorectal neoplasia (14 and 20 cases, respectively) and of sporadic rectal cancer cases (16) was analyzed immunohistochemically, as well as by immuno-fluorescence and electron microscopy. The results, heterogeneous phenotypes of Cygb+, αSMA+ and HSP47+ subepithelial myofibroblasts and interstitial cells, corresponding to rectal stellate cells, were demonstrated. A decrease of Cygb+ subepithelial myofibroblasts and an increase of αSMA+ interstitial cells were significant in UC, as compared to normal rectal mucosa. Furthermore, a decrease of Cygb+ subepithelial myofibroblasts, correlating with αSMA+ and HSP47+ cells, was significant in long-standing UC with neoplasia. In conclusion, there are heterogeneous phenotypes of Cygb+, αSMA+ and HSP47+ subepithelial myofibroblasts and interstitial cells in the rectal mucosa. Mucosal remodeling with alterations of Cygb+ and/or αSMA+/HSP47+ stromal cells might have some relation to UC-associated tumorigenesis

Unique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein

Dysregulated expression of L-type amino acid transporter 1 (LAT1), which transports large neutral amino acids, is a characteristic of various human cancers and possibly offers a molecular target for chemotherapy. LAT2, in contrast, shows lower expression in neoplasms. LAT1 is presumed to be a biomarker of many cancers, suggesting a kind of oncoprotein. However, no precise analysis of LAT1 and LAT2 expression has been performed in systemic normal tissues. To see characteristics of LAT1 and LAT2, immunohisto-chemical expression of LAT1 and LAT2 was assessed and compared in normal human systemic organs and tissues from 3 adults, 3 children and 3 fetuses in the present study. Cardiac muscles, hepatocytes, thymic epithelial cells and primitive neuroectodermal cells in fetus were positive with LAT1, whereas no expression was found in the respective adult tissues, indicating an aspect of oncofetal protein. In adult tissues, LAT1 was found to be expressed proximal to proliferative zones in gastrointestinal mucosa by double immunostaining of LAT1 and Ki-67. Testicular Sertoli cells, ovarian follicular cells, and pancreatic islet cells showed strong expression. Although the systemic capillary endothelium did not express LAT1, but did express LAT2, capillaries corresponding to the blood-brain, blood-follicle, and blood-retinal barriers demonstrated strong LAT1 immunoreactions. In conclusion, LAT1 was expressed in gonad tissues and several kinds of cells having special functions, as well as being discovered to be an aspect of oncofetal protein. In addition, ubiquitous LAT2 expression was confirmed immunohistochemically in systemic tissues, indicating constitutional function

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.11Nsciescopu

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

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 identify120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including16 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 factorSP4, 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

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