Population-specific haplotype association of the postsynaptic density gene DLG4 with schizophrenia, in family-based association studies.
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.
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
Shabeesh
S
Balan
Kazuo
K
Yamada
Eiji
E
Hattori
Yoshimi
Y
Iwayama
Tomoko
T
Toyota
Tetsuo
T
Ohnishi
Motoko
M
Maekawa
Manabu
M
Toyoshima
Yasuhide
Y
Iwata
Katsuaki
K
Suzuki
Mitsuru
M
Kikuchi
Takeo
T
Yoshikawa
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000483:Alleles; D044466:Asian People; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D057907:Post-Synaptic Density / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D013569:Synapses / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C513314:DLG1 protein, human; C501444:DLG4 protein, human; D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2