Population-Specific Haplotype Association of the Postsynaptic Density Gene DLG4 with Schizophrenia, in Family-Based Association Studies

• Published in: PloS one Vol. 8; no. 7; p. e70302
• Main Authors: Balan, Shabeesh, Yamada, Kazuo, Hattori, Eiji, Iwayama, Yoshimi, Toyota, Tomoko, Ohnishi, Tetsuo, Maekawa, Motoko, Toyoshima, Manabu, Iwata, Yasuhide, Suzuki, Katsuaki, Kikuchi, Mitsuru, Yoshikawa, Takeo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.07.2013; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Alleles; Asian Continental Ancestry Group; Association analysis; Biology; Bipolar disorder; Brain; Carrier Proteins - genetics; Case-Control Studies; Cognitive ability; Disks Large Homolog 4 Protein; Female; Gene expression; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic relationship; Genetic variance; Genetics; Glutamatergic transmission; Haplotypes; Humans; Intracellular Signaling Peptides and Proteins - genetics; Kinases; Laboratories; Male; MDM2 protein; Medical research; Medicine; Membrane Proteins - genetics; Mental disorders; Middle Aged; Nervous system diseases; Neurosciences; Nuclear Proteins - genetics; Pathogenesis; Pedigree; Polymorphism, Single Nucleotide; Population; Post-Synaptic Density - pathology; Postsynaptic density; Proteins; Proto-Oncogene Proteins c-mdm2 - genetics; Psychiatry; Rodents; Schizophrenia; Schizophrenia - ethnology; Schizophrenia - genetics; Schizophrenia - pathology; Science; Synapses; Synapses - pathology; Synaptic density; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0070302

The post-synaptic density (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects). Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02), although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects). The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively. However, this could not be replicated in case-control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes.