Dataset Information

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

ABSTRACT: In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

SUBMITTER: Juraeva D

PROVIDER: S-EPMC4046913 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

Juraeva Dilafruz D Haenisch Britta B Zapatka Marc M Frank Josef J Witt Stephanie H SH Mühleisen Thomas W TW Treutlein Jens J Strohmaier Jana J Meier Sandra S Degenhardt Franziska F Giegling Ina I Ripke Stephan S Leber Markus M Lange Christoph C Schulze Thomas G TG Mössner Rainald R Nenadic Igor I Sauer Heinrich H Rujescu Dan D Maier Wolfgang W Børglum Anders A Ophoff Roel R Cichon Sven S Nöthen Markus M MM Rietschel Marcella M Mattheisen Manuel M Brors Benedikt B

PLoS genetics 20140605 6

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and repli ...[more]

PMID: 24901509

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Project description:BackgroundLike human immunodeficiency virus (HIV), ovine lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection.Methodology/principal findingsThis genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P=9.2×10(-7); empirical P=0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1 × 10(-5)). Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P=0.006), and SYTL3 (P=0.051). Genes in regions associated with control of infection included a zinc finger cluster (ZNF192, ZSCAN16, ZNF389, and ZNF165; P=0.001), C19orf42/TMEM38A (P=0.047), and DLGAP1 (P=0.092).Conclusions/significanceThese associations provide targets for mutation discovery in sheep susceptibility to OvLV. Aside from TMEM154, these genes have not been associated previously with lentiviral infection in any species, to our knowledge. Further, data from other species suggest functional hypotheses for future testing of these genes in OvLV and other lentiviral infections. Specifically, SYTL3 binds and may regulate RAB27A, which is required for enveloped virus assembly of human cytomegalovirus. Zinc finger transcription factors have been associated with positive selection for repression of retroviral replication. DLGAP1 binds and may regulate DLG1, a known regulator of HIV infectivity.

Project description:The population growth trend in recent decades has resulted in continuing efforts to guarantee food security in which leguminous plants, such as the common bean (Phaseolus vulgaris L.), play a particularly important role as they are relatively cheap and have high nutritional value. To meet this demand for food, the main target for genetic improvement programs is to increase productivity, which is a complex quantitative trait influenced by many component traits. This research aims to identify Quantitative Trait Nucleotides (QTNs) associated with productivity and its components using multi-locus genome-wide association studies. Ten morpho-agronomic traits [plant height (PH), first pod insertion height (FPIH), number of nodules (NN), pod length (PL), total number of pods per plant (NPP), number of locules per pod (LP), number of seeds per pod (SP), total seed weight per plant (TSW), 100-seed weight (W100), and grain yield (YLD)] were evaluated in four environments for 178 Mesoamerican common bean domesticated accessions belonging to the Brazilian Diversity Panel. In order to identify stable QTNs, only those identified by multiple methods (mrMLM, FASTmrMLM, pLARmEB, and ISIS EM-BLASSO) or in multiple environments were selected. Among the identified QTNs, 64 were detected at least thrice by different methods or in different environments, and 39 showed significant phenotypic differences between their corresponding alleles. The alleles that positively increased the corresponding traits, except PH (for which lower values are desired), were considered favorable alleles. The most influenced trait by the accumulation of favorable alleles was PH, showing a 51.7% reduction, while NN, TSW, YLD, FPIH, and NPP increased between 18 and 34%. Identifying QTNs in several environments (four environments and overall adjusted mean) and by multiple methods reinforces the reliability of the associations obtained and the importance of conducting these studies in multiple environments. Using these QTNs through molecular techniques for genetic improvement, such as marker-assisted selection or genomic selection, can be a strategy to increase common bean production.

Dataset Information

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

Publications

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

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