title: Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1.
abstract: We have previously reported a robust association between an allelic haplotype of 'Disrupted in Schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
authors.forename: William
authors.initials: W
authors.lastname: Hennah
authors.forename: Liisa
authors.initials: L
authors.lastname: Tomppo
authors.forename: Tero
authors.initials: T
authors.lastname: Hiekkalinna
authors.forename: Outi M
authors.initials: OM
authors.lastname: Palo
authors.forename: Helena
authors.initials: H
authors.lastname: Kilpinen
authors.forename: Jesper
authors.initials: J
authors.lastname: Ekelund
authors.forename: Annamari
authors.initials: A
authors.lastname: Tuulio-Henriksson
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.forename: Timo
authors.initials: T
authors.lastname: Partonen
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Terwilliger
authors.forename: Jouko
authors.initials: J
authors.lastname: Lönnqvist
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D005387:Finland; D005799:Genes, Dominant; D005808:Genes, Recessive; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C412476:DISC1 protein, human; D005819:Genetic Markers; C421108:NDEL1 protein, human; D009419:Nerve Tissue Proteins