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Journal of Neural Transmission

, Volume 122, Issue 6, pp 915–923 | Cite as

Association study of H2AFZ with schizophrenia in a Japanese case–control sample

  • Daisuke Jitoku
  • Naoki Yamamoto
  • Yoshimi Iwayama
  • Tomoko Toyota
  • Momo Miyagi
  • Takeshi Enokida
  • Yuri Tasaka
  • Masakazu Umino
  • Asami Umino
  • Akihito Uezato
  • Yasuhide Iwata
  • Katsuaki Suzuki
  • Mitsuru Kikuchi
  • Tasuku Hashimoto
  • Nobuhisa Kanahara
  • Akeo Kurumaji
  • Takeo Yoshikawa
  • Toru NishikawaEmail author
Psychiatry and Preclinical Psychiatric Studies - Original Article

Abstract

It is widely accepted that malfunction of the N-methyl-d-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01–04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02–SNP03 (rs10014424)–SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.

Keywords

H2AFZ Histone acetylation miRNA Phencyclidine SNP Schizophrenia 

Abbreviations

miRNA

microRNA

H2AFZ

H2A histone family, member Z

SNP

Single nucleotide polymorphism

GWAS

Genome-wide association study

NMDA

N-methyl-d-aspartate

GLIN1

Glutamate receptor ionotropic N-methyl-d-aspartate 1

GLIN2A

Glutamate receptor ionotropic N-methyl-d-aspartate 2A

GLIN2B

Glutamate receptor ionotropic N-methyl-d-aspartate 2B

BDNF

Brain-derived neurotrophic factor

DRD1

Dopamine receptor 1

PCP

Phencyclidine

PCR

Polymerase chain reaction

Prt6

PCP-related transcript 6

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HDAC1

Class I histone deacetylase

HDAC2

Class II histone deacetylase

VPA

Valproic acid

HDACi

Histone deacetylase inhibitor

r2

Correlation coefficient

MAF

Minor allele frequency

LD

Linkage disequilibrium

HWE

Hardy–Weinberg equilibrium

D′

Standardized disequilibrium coefficient

OR

Odds ratio

95 % CI

95 % confidence interval

SAP97 SNP

Single nucleotide polymorphism Synapse-associated protein 97

DISC1

Disrupted-in-schizophrenia 1

RELN

Reelin

DAO

d-amino acid oxidase

Notes

Acknowledgments

We thank all subjects who participated in this study. We also thank Drs. Kazuo Yamada and Eiji Hattori for recruitment of the samples. The present study is the result of “Development of biomarker candidates for social behavior” carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

702_2014_1332_MOESM1_ESM.xls (58 kb)
Supplementary material 1 (XLS 57 kb)

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Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Daisuke Jitoku
    • 1
  • Naoki Yamamoto
    • 1
  • Yoshimi Iwayama
    • 2
  • Tomoko Toyota
    • 2
  • Momo Miyagi
    • 1
  • Takeshi Enokida
    • 1
  • Yuri Tasaka
    • 1
  • Masakazu Umino
    • 1
  • Asami Umino
    • 1
  • Akihito Uezato
    • 1
  • Yasuhide Iwata
    • 3
  • Katsuaki Suzuki
    • 3
  • Mitsuru Kikuchi
    • 4
  • Tasuku Hashimoto
    • 5
  • Nobuhisa Kanahara
    • 5
  • Akeo Kurumaji
    • 1
  • Takeo Yoshikawa
    • 1
    • 2
  • Toru Nishikawa
    • 1
    Email author
  1. 1.Department of Psychiatry and Behavioral SciencesTokyo Medical and Dental University Graduate SchoolTokyoJapan
  2. 2.Laboratory for Molecular PsychiatryRIKEN Brain Science InstituteWakoJapan
  3. 3.Department of Psychiatry and NeurologyHamamatsu University School of MedicineShizuokaJapan
  4. 4.Department of Psychiatry and NeurobiologyKanazawa University Graduate School of MedicineKanazawaJapan
  5. 5.Department of Psychiatry, Graduate School of MedicineChiba UniversityChibaJapan

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