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  • 1
    Keywords: PATHWAYS ; DISEASES ; GENE ; COMPLEX ; RESPONSES ; FAMILY ; VARIANTS ; AUTOIMMUNITY ; SCAN ; STATISTICAL-METHOD
    Abstract: To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P 〈 5 x 10(-)(8) and two loci with a combined P 〈 5 x 10(-)(7)). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 x 10(-)(6)). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
    Type of Publication: Journal article published
    PubMed ID: 20953190
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  • 2
    Keywords: DISEASES ; GENE-EXPRESSION ; TRANSPORT ; MOTIF ; GAMMA ; ANNOTATION ; COMMON VARIANTS ; WIDE ASSOCIATION ; HAPMAP ; ENRICHMENT ANALYSIS
    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.
    Type of Publication: Journal article published
    PubMed ID: 24901509
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  • 3
    Publication Date: 2013-08-21
    Description: The development of multicellular animals is initially controlled by maternal gene products deposited in the oocyte. During the maternal-to-zygotic transition, transcription of zygotic genes commences, and developmental control starts to be regulated by zygotic gene products. In Drosophila, the transcription factor Zelda specifically binds to promoters of the earliest zygotic genes and primes them for activation. It is unknown whether a similar regulation exists in other animals. We found that zebrafish Pou5f1, a homolog of the mammalian pluripotency transcription factor Oct4, occupies SOX-POU binding sites before the onset of zygotic transcription and activates the earliest zygotic genes. Our data position Pou5f1 and SOX-POU sites at the center of the zygotic gene activation network of vertebrates and provide a link between zygotic gene activation and pluripotency control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leichsenring, Manuel -- Maes, Julia -- Mossner, Rebecca -- Driever, Wolfgang -- Onichtchouk, Daria -- New York, N.Y. -- Science. 2013 Aug 30;341(6149):1005-9. doi: 10.1126/science.1242527. Epub 2013 Aug 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Biology Unit, Institute Biology I, Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23950494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; DNA Polymerase II/metabolism ; *Gene Expression Regulation, Developmental ; Octamer Transcription Factor-3/genetics/*metabolism ; Pluripotent Stem Cells/cytology/physiology ; SOXB1 Transcription Factors/metabolism ; *Transcriptional Activation ; Xenopus Proteins/metabolism ; Zebrafish/*embryology/genetics ; Zebrafish Proteins/genetics/*metabolism ; Zygote/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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