The authors have no conflict of interest to declare.
Version of Record online: 14 MAR 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 159B, Issue 4, pages 392–404, June 2012
How to Cite
Verbrugghe, P., Bouwer, S., Wiltshire, S., Carter, K., Chandler, D., Cooper, M., Morar, B., Razif, M. F.M., Henders, A., Badcock, J. C., Dragovic, M., Carr, V., Almeida, O. P., Flicker, L., Montgomery, G., Jablensky, A. and Kalaydjieva, L. (2012), Impact of the Reelin signaling cascade (Ligands–Receptors–Adaptor Complex) on cognition in schizophrenia. Am. J. Med. Genet., 159B: 392–404. doi: 10.1002/ajmg.b.32042
Phebe Verbrugghe and Sonja Bouwer contributed equally to this work.
How to Cite this Article: Verbrugghe P, Bouwer S, Wiltshire S, Carter K, Chandler D, Cooper M, Morar B, Razif MFM, Henders A, Badcock JC, Dragovic M, Carr V, Almeida OP, Flicker L, Montgomery G, Jablensky A, Kalaydjieva L. 2012. Impact of the Reelin Signaling Cascade (Ligands–Receptors–Adaptor Complex) on Cognition in Schizophrenia. Am J Med Genet Part B 159B:392–404.
- Issue online: 7 MAY 2012
- Version of Record online: 14 MAR 2012
- Manuscript Accepted: 17 FEB 2012
- Manuscript Received: 26 OCT 2011
- National Health and Medical Research Council of Australia. Grant Numbers: 37580400, 37580900, 964145, 139093, 403963, 455811
- cognitive deficit;
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. © 2012 Wiley Periodicals, Inc.