title: Role of DISC1 interacting proteins in schizophrenia risk from genome-wide analysis of missense SNPs.
abstract: A balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein-protein interactions involved in multiple developmental pathways within the brain. Gene set-based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome-wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome-wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P-value=0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading-edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.
authors.affiliation: Servizo Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago, Complexo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Costas
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Suárez-Rama
authors.forename: Noa
authors.initials: N
authors.lastname: Carrera
authors.forename: Eduardo
authors.initials: E
authors.lastname: Paz
authors.forename: Mario
authors.initials: M
authors.lastname: Páramo
authors.forename: Santiago
authors.initials: S
authors.lastname: Agra
authors.forename: Julio
authors.initials: J
authors.lastname: Brenlla
authors.forename: Ramón
authors.initials: R
authors.lastname: Ramos-Ríos
authors.forename: Manuel
authors.initials: M
authors.lastname: Arrojo
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D019295:Computational Biology; D066264:Datasets as Topic; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012306:Risk; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins
keywords: Psychosis; actin cytoskeleton; axonal transport; gene set enrichment; pathway analysis