Circadian Rhythms Correlated in DNA Methylation and Gene Expression Identified in Human Blood and Implicated in Psychiatric Disorders

Abstract

Circadian rhythms modulate the biology of many human tissues and are driven by a nearly 24-h transcriptional feedback loop. Dynamic DNA methylation may play a role in driving 24-h rhythms of gene expression in the human brain. However, little is known about the degree of circadian regulation between the DNA methylation and the gene expression in the peripheral tissues, including human blood. We hypothesized that 24-h rhythms of DNA methylation play a role in driving 24-h RNA expression in human blood. To test this hypothesis, we analyzed DNA methylation levels and RNA expression in blood samples collected from eight healthy males at six-time points over 24 h. We assessed 442,703 genome-wide CpG sites in methylation and 12,364 genes in expression for 24-h rhythmicity using the cosine model. Our analysis revealed significant rhythmic patterns in 6345 CpG sites and 21 genes. Next, we investigated the relationship between methylation and expression using powerful circadian signals. We found a modest negative correlation (ρ = −0.83, p = 0.06) between the expression of gene TXNDC5 and the methylation at the nearby CpG site (cg19116172). We also observed that circadian CpGs significantly overlapped with genetic risk loci of schizophrenia and autism spectrum disorders. Notably, one gene, TXNDC5, showed a significant correlation between circadian methylation and expression and has been reported to be association with neuropsychiatric diseases.