Genetic and molecular risk factors within the newly identified primate‐specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia‐associated locus

Abstract

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

Association of the Synapse-Associated Protein 97 (SAP97) Gene Polymorphism With Neurocognitive Function in Schizophrenic Patients

“…In this study, we have assessed the potential association of the rs3915512 polymorphism of the SAP97 gene with schizophrenia. However, the results revealed that there was no significant difference in genotype and allele distributions between the patients with schizophrenia and the healthy controls ( P > 0.05), which was inconsistent with the results of a previous Japanese cohort study from the Hondo area by Uezato et al ( 12 ). Moreover, the allelic frequencies of rs3915512 in the present study (A:T = 0.29: 0.71 in the cases and A:T = 0.28:0.72 in the controls), were markedly different from those in the Japanese Hondo cohort from a previous study (A:T = 0.63:0.37 in the cases and A:T = 0.66: 0.34 in the controls) ( 12 ).…”

“…In addition, studies have shown that changing the structure of SAP97 would alter the binding affinity with its ligands and affect the transport of glutamate ( 11 ), which has been identified to play a key role in schizophrenia ( 6 ). A recent Japanese case-control study provided evidence of the relationship between the rs3915512 polymorphism of the SAP97 gene and schizophrenia ( 12 ). However, SAP97 gene polymorphisms have not been studied in schizophrenia patients of the Han Chinese population.…”

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

“…DLG1 has previously been associated with schizophrenia (Sato, Shimazu, Yamamoto, & Nishikawa, ; Toyooka et al, ; Uezato et al, , , ). The variant found in our patient was identified in a study of 234 unrelated cases with schizophrenia and 272 unrelated controls from the United Kingdom (Carroll et al, ).…”

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

“…including those with roles in neuron proliferation, differentiation, cell-cell interaction, intraneuronal transport, synaptogenesis, primary axonogenesis, and axon guidance (Dlg1,Myt1l,Ptprs,Dctn2,Rgs7). Further, some genes are genetically linked to psychiatric disorders such as schizophrenia (Dlg1, Myt1l) (Lee et al, 2012;Uezato et al, 2017), autism spectrum disorder (Myt1l) (Meyer et al, 2012;Wang et al, 2016) and panic disorder (Rgs7) (Hohoff et al, 2009). Other genes from this list are linked to various types of cancer (Pnck,Calu,Vav2,Kif3a,Adgrf5,N4bp2l2).…”