title: Genetic analysis of the glyoxalase system in schizophrenia.
abstract: Recent reports suggest that carbonyl stress might affect a subset of schizophrenia patients suffering from severe symptoms. Carbonyl stress protection is achieved by the glyoxalase system consisting of two enzymes, glyoxalase 1 and 2, which in humans are encoded by the genes GLO1 and HAGH, respectively. Glyoxalase 1 and 2 catalyze the detoxification of reactive alpha-oxoaldehydes such as glyoxal and methylglyoxal, which are particularly damaging components of carbonyl stress. Here, we investigated the role of the glyoxalase system in schizophrenia by performing association analyses of common genetic variants (n=12) in GLO1 and HAGH in a Japanese sample consisting of 2012 schizophrenia patients and 2170 healthy controls. We detected a nominally significant association with schizophrenia (p=0.020) of rs11859266, a SNP in the intronic region of HAGH. However, rs11859266 did not survive multiple testing (empirical p=0.091). The variants in HAGH, rs11859266 and rs3743852, showed significant associations with schizophrenia in males at allelic and genotype levels, which remained persistent after multiple testing with the exception of rs3743852 for the genotype model. We further measured the mRNA expression of both genes in postmortem brain, but did not detect any changes in transcript expression levels between case and control samples or in sex-specific comparisons. Therefore, our findings suggest that an explanation of elevated carbonyl stress in a substantial part (reported as ~20%) of patients with schizophrenia will require the examination of a much larger cohort to detect risk alleles with weak effect size and/or other risk factors.
authors: Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors: Fabian N
authors: FN
authors: Bangel
authors: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors: Kazuo
authors: K
authors: Yamada
authors: Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors: Makoto
authors: M
authors: Arai
authors: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors: Yoshimi
authors: Y
authors: Iwayama
authors: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors: Shabeesh
authors: S
authors: Balan
authors: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors: Tomoko
authors: T
authors: Toyota
authors: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors: Yasuhide
authors: Y
authors: Iwata
authors: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors: Katsuaki
authors: K
authors: Suzuki
authors: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors: Mitsuru
authors: M
authors: Kikuchi
authors: Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Tasuku
authors: T
authors: Hashimoto
authors: Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Nobuhisa
authors: N
authors: Kanahara
authors: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors: Norio
authors: N
authors: Mori
authors: Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors: Masanari
authors: M
authors: Itokawa
authors: Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors: Oliver
authors: O
authors: Stork
authors: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan. Electronic address: takeo@brain.riken.jp.
authors: Takeo
authors: T
authors: Yoshikawa
mesh_terms: D000328:Adult; D001921:Brain / Q000201:enzymology / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000145:classification / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D012737:Sex Factors; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000378:metabolism; D000099301:Hydroxyacylglutathione Hydrolase
chemical_list: D007791:Lactoylglutathione Lyase; D012333:RNA, Messenger; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase
keywords: GLO1; HAGH (GLO2); association study; carbonyl stress; schizophrenia