Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene

Abstract

Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3'UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology.

Molecular Characterization of Disrupted in Schizophrenia-1 Risk Variant S704C Reveals the Formation of Altered Oligomeric Assembly

“…Although its impact on disease pathogenesis is debated (10,27), its connection to schizophrenia is credible (28), and its importance in corticogenesis is widely accepted (3,17,29). Likewise, evidence (30,31) associating NDEL1 to schizophrenia biology is debated (32). However, the crucial role of NDEL1, together with DISC1 in cortical layer formation (17,29), is well established.…”

Expression of Human MDGA1 Increases Cell Motility and Cell-Cell Adhesion and Reduces Adhesion to Extracellular Matrix Proteins in MDCK Cells

“…Consistent with this, in the last few years both MDGA1 and MDGA2 have been implicated in human neurodevelopmental syndromes. MDGA1 has been proposed as a new schizophrenia susceptibility gene involved in neuronal migration [35], meanwhile MDGA2 has been postulated as a novel autism susceptibility gene that shows a high similarity to contactin 4 (CNTN4), which has also been linked to this disease [36]. Moreover, MDGA1 expression has been found to be altered in tumor tissues [3,37].…”

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

“…Knockout of MDGA1 causes a discrete phenotype in neuronal migration and impairs rostral growth of commissural axons, suggesting an important role during the initial development of the brain (17,18). Interestingly, SNP-based, large-scale human genetic analyses suggested that MDGA1 and MDGA2 may be susceptibility genes for schizophrenia, bipolar disorder, and autism spectrum disorder (19)(20)(21). However, despite continued high-level expression of MDGAs in adult brain, their functions in mature neurons remain unknown.…”