title: Impact of the Reelin signaling cascade (ligands-receptors-adaptor complex) on cognition in schizophrenia.
abstract: Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects--cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of Schizophrenia (WAFSS) was followed by replication analysis in the Australian Schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia.
authors.affiliation: Centre for Medical Research, Western Australian Institute for Medical Research, The University of Western Australia, Perth, Australia.
authors.forename: Phebe
authors.initials: P
authors.lastname: Verbrugghe
authors.forename: Sonja
authors.initials: S
authors.lastname: Bouwer
authors.forename: Steven
authors.initials: S
authors.lastname: Wiltshire
authors.forename: Kim
authors.initials: K
authors.lastname: Carter
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Matthew
authors.initials: M
authors.lastname: Cooper
authors.forename: Bharti
authors.initials: B
authors.lastname: Morar
authors.forename: Muhammad F M
authors.initials: MF
authors.lastname: Razif
authors.forename: Anjali
authors.initials: A
authors.lastname: Henders
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Badcock
authors.forename: Milan
authors.initials: M
authors.lastname: Dragovic
authors.forename: Vaughan
authors.initials: V
authors.lastname: Carr
authors.forename: Osvaldo P
authors.initials: OP
authors.lastname: Almeida
authors.forename: Leon
authors.initials: L
authors.lastname: Flicker
authors.forename: Grant
authors.initials: G
authors.lastname: Montgomery
authors.forename: Assen
authors.initials: A
authors.lastname: Jablensky
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001057:Apolipoproteins E / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D008024:Ligands; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D011973:Receptors, LDL / Q000235:genetics*; D000091042:Reelin Protein; D015203:Reproducibility of Results; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014904:Western Australia
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D015816:Cell Adhesion Molecules, Neuronal; C115785:DAB1 protein, human; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; D012697:Serine Endopeptidases