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Background: The results of meta-analyses conducted by previous association studies between total homocysteine and schizophrenia suggest that an elevated total homocysteine level is a risk factor for schizophrenia. However, observational studies have potential limitations, such as confounding and reverse causation. In the present study, we evaluated a causal relationship between plasma total homocysteine and schizophrenia by conducting a Mendelian randomization analysis., Methods: We used the MTHFR C677T polymorphism as an instrumental variable, which affects the plasma total homocysteine levels. To calculate the risk estimate for the association of this single nucleotide polymorphism (SNP) with schizophrenia, we conducted a meta-analysis of case-control studies that comprise a total of 11,042 patients with schizophrenia and 14,557 control subjects. We obtained an estimate for the association of this SNP with the plasma total homocysteine levels from a meta-analysis of genome-wide association studies comprising 44,147 individuals., Results: By combining these two estimates, we demonstrated a significant effect of the plasma total homocysteine on schizophrenia risk, representing an OR of 2.15 (95 % CI = 1.39-3.32; p = 5.3 x 10(-4)) for schizophrenia per 1-SD increase in the natural log-transformed plasma total homocysteine levels., Conclusions: We provided evidence of a causal relationship between the plasma total homocysteine and schizophrenia, and this result will add insight into the pathology and treatment of schizophrenia.

Background: DNA methylation, which is most frequently the transference of a methyl group to the 5-carbon position of the cytosine in a CpG dinucleotide, plays an important role in both normal development and diseases. To date, several genome-wide methylome studies have revealed sex-biased DNA methylation, yet no studies have investigated sex differences in DNA methylation by taking into account cellular heterogeneity. The aim of the present study was to investigate sex-biased DNA methylation on the autosomes in human blood by adjusting for estimated cellular proportions because cell-type proportions may vary by sex., Methods: We performed a genome-wide DNA methylation profiling of the peripheral leukocytes in two sets of samples, a discovery set (49 males and 44 females) and a replication set (14 males and 10 females) using Infinium HumanMethylation450 BeadChips for 485,764 CpG dinucleotides and then examined the effect of sex on DNA methylation with a multiple linear regression analysis after adjusting for age, the estimated 6 cell-type proportions, and the covariates identified in a surrogate variable analysis., Results: We identified differential DNA methylation between males and females at 292 autosomal CpG site loci in the discovery set (Bonferroni-adjusted p < 0.05). Of these 292 CpG sites, significant sex differences were also observed at 98 sites in the replication set (p < 0.05)., Conclusions: These findings provided further evidence that DNA methylation may play a role in the differentiation or maintenance of sexual dimorphisms. Our methylome mapping of the effects of sex may be useful to understanding the molecular mechanism involved in both normal development and diseases.