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.

The involvement of Reelin in neurodevelopmental disorders

“…A separate study, however, found that RELN SNP rs7341475 was not associated with deficits in working memory, Reelin mRNA expression in brain, or brain structure (Tost et al 2010). Finally, a recent study found significant associations between SNPs of APOE, APOER2, VLDLR, and DAB1 with cognitive performance of subjects with schizophrenia while there was no such association for RELN (Verbrugghe et al 2012). Additionally, in a second cohort of normal aging males, the authors found associations between SNPs of APOE and APOER2 with memory performance.…”

Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia

“…This gene exerted the most significant signal in haploPS (P unadjusted = 6.92E-09; P adjusted = 0.0007) and F ST (P = 2.43E-08), and it plays a central role in the brain development and normal cognitive function (Li et al 2013;Verbrugghe et al 2012). Interestingly, animal study suggested that this gene may play a protective role against cerebral malaria (Delahaye et al 2007), however, it has not been reported in human study.…”

Altered apolipoprotein C expression in association with cognition impairments and hippocampus volume in schizophrenia and bipolar disorder

“…The involvement of altered Apo levels in decreased cognitive performance or cognitive decline has been proposed previously (Dassati et al, 2014;Elliott et al, 2010;Huang & Mahley, 2014;La et al, 2007), but has not yet been thoroughly investigated in SZ or BD. A study by Verbrugghe et al (Verbrugghe et al, 2012) conducted an association analysis between disease outcome and cognitive performance in SZ. They described that ApoE, ApoER2, VLDLR, and DAB1 SNPs were significantly related to disease outcome, pre-morbid intelligence and verbal memory.…”

“…However, this link between cognitive impairments and Apo levels has not been done for SZ or BD, so far. A study by Verbrugghe and colleagues conducted and replicated a genetic association analysis between disease outcome and cognitive performance in SZ (Verbrugghe et al, 2012). They reported that ApoE, ApoER2, very-low-density-lipoprotein receptor (VLDLR) and disabled-1 (DAB1) single nucleotide polymorphisms (SNPs) were significantly associated with disease outcome, pre-morbid intelligence and verbal memory.…”