title: Targeted resequencing of regulatory regions at schizophrenia risk loci: Role of rare functional variants at chromatin repressive states.
abstract: There is mounting evidence that regulatory variation plays an important role in genetic risk for schizophrenia. Here, we specifically search for regulatory variants at risk by sequencing promoter regions of twenty-three genes implied in schizophrenia by copy number variant or genome-wide association studies. After strict quality control, a total of 55,206bp per sample were analyzed in 526 schizophrenia cases and 516 controls from Galicia, NW Spain, using the Applied Biosystems SOLiD System. Variants were filtered based on frequency from public databases, chromatin states from the RoadMap Epigenomics Consortium at tissues relevant for schizophrenia, such as fetal brain, mid-frontal lobe, and angular gyrus, and prediction of functionality from RegulomeDB. The proportion of rare variants at polycomb repressive chromatin state at relevant tissues was higher in cases than in controls. The proportion of rare variants with predicted regulatory role was significantly higher in cases than in controls (P=0.0028, OR=1.93, 95% C.I.=1.23-3.04). Combination of information from both sources led to the identification of an excess of carriers of rare variants with predicted regulatory role located at polycomb repressive chromatin state at relevant tissues in cases versus controls (P=0.0016, OR=19.34, 95% C.I.=2.45-2495.26). The variants are located at two genes affected by the 17q12 copy number variant, LHX1 and HNF1B. These data strongly suggest that a specific epigenetic mechanism, chromatin remodeling by histone modification during early development, may be impaired in a subset of schizophrenia patients, in agreement with previous data.
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Peñas
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Complexo Hospitalario Universitario de Santiago (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Amigo
authors.affiliation: Fundación Pública Galega de Medicina Xenómica, Complexo Hospitalario Universitario de Santiago (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Santomé
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Complexo Hospitalario Universitario de Santiago (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sobrino
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Servizo de Psiquiatría, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Brenlla
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Servizo de Psiquiatría, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Agra
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Servizo de Psiquiatría, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Paz
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Servizo de Psiquiatría, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Páramo
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Complexo Hospitalario Universitario de Santiago (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain; Servizo de Psiquiatría, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Arrojo
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain. Electronic address: javier.costas.costas@sergas.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Costas
mesh_terms: D001921:Brain / Q000254:growth & development / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000378:metabolism; D057890:Epigenomics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D008297:Male; D012045:Regulatory Sequences, Nucleic Acid; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: C496495:HNF1B protein, human; C085473:LHX1 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta
keywords: CNV; Chromatin remodeling; Next-generation sequencing; Polycomb; Rare variant; Single nucleotide variant