A Whole Methylome CpG-SNP Association Study of Psychosis in Blood and Brain Tissue.

Mutated CpG sites (CpG-SNPs) are potential hotspots for human diseases because in addition to the sequence variation they may show individual differences in DNA methylation. We performed methylome-wide association studies (MWAS) to test whether methylation differences at those sites were associated with schizophrenia. We assayed all common CpG-SNPs with methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) using DNA extracted from 1408 blood samples and 66 postmortem brain samples (BA10) of schizophrenia cases and controls. Seven CpG-SNPs passed our FDR threshold of 0.1 in the blood MWAS. Of the CpG-SNPs methylated in brain, 94% were also methylated in blood. This significantly exceeded the 46.2% overlap expected by chance (P-value < 1.010(-8)) and justified replicating findings from blood in brain tissue. CpG-SNP rs3796293 in IL1RAP replicated (P-value = .003) with the same direction of effects. This site was further validated through targeted bisulfite pyrosequencing in 736 independent case-control blood samples (P-value < 9.510(-4)). Our top result in the brain MWAS (P-value = 8.810(-7)) was CpG-SNP rs16872141 located in the potential promoter of ENC1. Overall, our results suggested that CpG-SNP methylation may reflect effects of environmental insults and can provide biomarkers in blood that could potentially improve disease management.

van den Oord, E., Clark, S. L., Xie, L. Y., Shabalin, A. A., Dozmorov, M. G., Kumar, G., ... Aberg, K. A.

van den Oord, Edwin JCG||Clark, Shaunna L||Xie, Lin Ying||Shabalin, Andrey A||Dozmorov, Mikhail G||Kumar, Gaurav||Vladimirov, Vladimir I||Magnusson, Patrik KE||Aberg, Karolina A

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