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.
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http://dx.doi.org/10.1002/ajmg.b.32042 | DOI Listing |
Brain Behav Immun
November 2024
Mike Petryk School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Women and Children Health Research Institute, University of Alberta, Edmonton T6G 2E1, AB, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2E1, AB, Canada; Glycomics Institute of Alberta, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, AB, Canada. Electronic address:
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Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China.
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Department of KM Science Research, Korea Institute of Oriental Medicine (KIOM), Daejeon 34054, Republic of Korea.
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J Biomed Sci
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Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, Taipei, 11031, Taiwan.
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