title: Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain.
abstract: Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p=1.7×10(-4), Allelic odds ratio=1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p<0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis.
authors.affiliation: CIBERSAM, Spain; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ivorra
authors.affiliation: CIBERSAM, Spain; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Rivero
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Complexo Hospitalario Universitario de Santiago (CHUS), Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Costas
authors.affiliation: Fundación Sant Joan de Deu, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Iniesta
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Complexo Hospitalario Universitario de Santiago (CHUS), Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Arrojo
authors.affiliation: Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Complexo Hospitalario Universitario de Santiago (CHUS), Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Ramos-Ríos
authors.affiliation: Grupo de Medicina Xenómica, Fundación Pública Galega de Medicina Xenómica, Universidad de Santiago de Compostela, CIBERER, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: CIBERSAM, Spain; Instituto de Investigación Hospital, Universitario 12 de Octubre, Psychiatry Department, Madrid, Spain.
authors.forename: Tomas
authors.initials: T
authors.lastname: Palomo
authors.affiliation: CIBERSAM, Spain; Instituto de Investigación Hospital, Universitario 12 de Octubre, Psychiatry Department, Madrid, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rodriguez-Jimenez
authors.affiliation: CIBERSAM, Spain; Centre for Public Mental Health, Health Services and Population Research Department, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cervilla
authors.affiliation: CIBERSAM, Spain; Universidad de Granada, Facultad de Medicina, Granada, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Gutiérrez
authors.affiliation: CIBERSAM, Spain; Universidad de Granada, Facultad de Medicina, Granada, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Molina
authors.affiliation: CIBERSAM, Spain; Child and Adolescent Psychiatry Department, Instituto de Investigación Sanitaria Gregorio Marañón, IiSGM, Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Celso
authors.initials: C
authors.lastname: Arango
authors.affiliation: CIBERSAM, Spain; Child and Adolescent Psychiatry Department, Instituto de Investigación Sanitaria Gregorio Marañón, IiSGM, Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: CIBERSAM, Spain; Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Pascual
authors.affiliation: CIBERSAM, Spain; Institut de Neuropsiquiatria i Addicions, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez
authors.affiliation: CIBERSAM, Spain; Área de Psiquiatría, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Pilar Alejandra
authors.initials: PA
authors.lastname: Saiz
authors.affiliation: CIBERSAM, Spain; Área de Psiquiatría, Universidad de Oviedo, Oviedo, Spain.
authors.forename: María Paz
authors.initials: MP
authors.lastname: García-Portilla
authors.affiliation: CIBERSAM, Spain; Área de Psiquiatría, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Bobes
authors.affiliation: CIBERSAM, Spain; Hospital Santiago Apostol de Vitoria, Vitoria, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: González-Pinto
authors.affiliation: CIBERSAM, Spain; Hospital Santiago Apostol de Vitoria, Vitoria, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Zorrilla
authors.affiliation: CIBERSAM, Spain; Fundación Sant Joan de Deu, Barcelona, Spain.
authors.forename: Josep María
authors.initials: JM
authors.lastname: Haro
authors.affiliation: CIBERSAM, Spain; Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona. Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Bernardo
authors.affiliation: CIBERSAM, Spain; Department of Psychiatry, Jimenez Diaz Foundation, Universidad Autonoma de Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Baca-García
authors.affiliation: CIBERSAM, Spain; Hospital Clinic, University of Valencia, INCLIVA, Valencia, Spain.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: González
authors.affiliation: CIBERSAM, Spain; Instituto de Investigación Hospital, Universitario 12 de Octubre, Psychiatry Department, Madrid, Spain; Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Janet
authors.initials: J
authors.lastname: Hoenicka
authors.affiliation: CIBERSAM, Spain; Departamento de Genética, Facultad de Biología, Universidad de Valencia, INCLIVA, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Moltó
authors.affiliation: CIBERSAM, Spain; Hospital Clinic, University of Valencia, INCLIVA, Valencia, Spain. Electronic address: Julio.sanjuan@uv.es.
authors.forename: Julio
authors.initials: J
authors.lastname: Sanjuán
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012559:Schizophrenia / Q000235:genetics*; D013030:Spain; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D008562:Membrane Glycoproteins; C576539:TENM4 protein, human
keywords: Bipolar disorder; GWAS; ODZ4; Polygenic score; Replication study; Schizophrenia