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.

• Authors: Akihito Uezato, Naoki Yamamoto, Daisuke Jitoku, Emiko Haramo, Eri Hiraaki, Yoshimi Iwayama, Tomoko Toyota, Masakazu Umino, Asami Umino, Yasuhide Iwata, Katsuaki Suzuki, Mitsuru Kikuchi, Tasuku Hashimoto, Nobuhisa Kanahara, Akeo Kurumaji, Takeo Yoshikawa, Toru Nishikawa
• Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (Am J Med Genet B Neuropsychiatr Genet) Vol. 174 Issue 8 Pg. 798-807 (Dec 2017) ISSN: 1552-485X [Electronic] United States
• PMID: 28990294 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• DLG1 protein, human
• Discs Large Homolog 1 Protein
• Membrane Proteins

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adult
• Age of Onset
• Brain
• Case-Control Studies
• Chromosomes, Human, Pair 3
• Discs Large Homolog 1 Protein
• Exons
• Female
• Genetic Loci
• Genetic Predisposition to Disease
• Genetic Testing
• Humans
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Risk Factors
• Schizophrenia (diagnosis, genetics)