Comprehensive genetic association analysis of genes from the Reelin and DISC1 networks in schizophrenia and neurocognitive endophenotypes

[Truncated abstract] Schizophrenia features phenotypic pleomorphism and may harbour genetically distinct variants obscured by broad diagnostic criteria. Targeting cognitive dysfunction, we defined two schizophrenia subtypes – cognitively spared (CS), and cognitive deficit (CD) with characteristics pointing to developmental origins and impaired synaptic plasticity. Neurocognitive tests measuring cognitive function can be used as endophenotypes of schizophrenia. The Ligand (ApoE/Reelin)-Receptor (ApoER2/VLDLR)-Adaptor (DAB1) complex (LRAC) and “DISC1 interactome” (ATF4, ATF5, CDK5, CITRON, DCX, DLG2, DLG4, FEZ1, LIS1, MAP1A, NUDE, NUDEL, PDE4B), involved in brain development and synaptic plasticity may confer susceptibility to schizophrenia with a differential contribution to the CD vs. the CS subtype. Methods: Association analyses was performed using 503 and 472 tSNPs, comprehensively covering the LRAC and DISC1 interactome genes respectively, in three case/control datasets (Schizophrenia/Controls, CD/Controls, CS/Controls) and with neurocognitive measures (Continuous performance Task, identical-pairs and degraded-stimulus versions; Rey Auditory Verbal learning test; National Adult Reading Test; Shipley Institute of Living Scale) in 336 schizophrenia cases and 172 controls. Association analysis of pairwise SNP interactions was performed in the case/control datasets and using quantitative traits. Results: In the LRAC genes, significant association after correction for multiple testing was observed between schizophrenia and rs439401 (ApoE; corrected P=0.04), rs1454626 (VLDLR; corrected P=0.05). Significant association was also found between CD and rs1454626 (VLDLR; corrected P=0.05). VLDLR iii mRNA levels were reduced in schizophrenia and CD cells.