Population-dependent contribution of the major histocompatibility complex region to schizophrenia susceptibility.
There is consistent data from European cohorts suggesting a genetic contribution from the major histocompatibility complex (MHC) to the pathogenesis of schizophrenia. However, the genomic complexity and ethnicity-specific diversity found in the MHC cause difficulties in identifying causal variants or genes, and there is a need for studies encompassing the entire MHC region in multiple ethnic populations. Here, we report on association signals in the MHC region, with schizophrenia in the Japanese population. We genotyped and imputed a total of 10,131 single nucleotide polymorphisms (SNPs), spanning the entire MHC interval. The analysis included 3302 participants (1518 schizophrenics and 1784 healthy controls) from the Japanese population. In this study, we present evidence for association at rs494620, located in the SLC44A4 gene. The association survived after correction for multiple testing (unadjusted P=7.78×10(-5), empirical P=0.0357). The imputation results detected the highest association at rs707937 in the MSH5-SAPCD1 gene (imputed P=8.40×10(-5)). In expression analysis using postmortem brains from schizophrenia and control samples, MSH5-SAPCD1 showed marginally significant expression differences in Brodmann's area 46 (P=0.044 by unpaired t test with Welch's correction, P=0.099 by Mann-Whitney U test). Our study further strengthens evidence for the involvement of the MHC in schizophrenia across populations, and provides insight into population-specific mechanisms for the MHC region in schizophrenia susceptibility.
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Kazuo
K
Yamada
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Eiji
E
Hattori
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Yoshimi
Y
Iwayama
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Tomoko
T
Toyota
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
Yasuhide
Y
Iwata
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
Katsuaki
K
Suzuki
Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8641, Japan.
Mitsuru
M
Kikuchi
Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Tasuku
T
Hashimoto
Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Nobuhisa
N
Kanahara
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
Norio
N
Mori
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan. Electronic address: takeo@brain.riken.jp.
Takeo
T
Yoshikawa
D000328:Adult; D044466:Asian People / Q000235:genetics; D001921:Brain / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000502:physiology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
D026901:Membrane Transport Proteins; C583905:SLC44A4 protein, human
Association study; Major histocompatibility complex; Schizophrenia; Single nucleotide polymorphism; Solute carrier family 44 member 4; mutS homolog 5-suppressor APC domain containing 1