Genetic analysis of the glyoxalase system in schizophrenia

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.