title: A Whole Methylome CpG-SNP Association Study of Psychosis in Blood and Brain Tissue.
abstract: 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 < 1.0×10(-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 < 9.5×10(-4)). Our top result in the brain MWAS (P-value = 8.8×10(-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.
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA; ejvandenoord@vcu.edu.
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA;
authors.forename: Shaunna L
authors.initials: SL
authors.lastname: Clark
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA;
authors.forename: Lin Ying
authors.initials: LY
authors.lastname: Xie
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA;
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Shabalin
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, VA;
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Dozmorov
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA;
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA; Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD;
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Vladimirov
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA;
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Aberg
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D008840:Microfilament Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C112302:ectodermal-neural cortex 1 protein
keywords: DNA methylation; MBD-seq; SNPs; methylome-wide association study; postmortem brain samples; psychosis