TY - JOUR
T1 - A whole methylome CpG-SNP association study of psychosis in blood and brain tissue
AU - Van Den Oord, Edwin J. C. G.
AU - Clark, Shaunna L.
AU - Xie, Lin Ying
AU - Shabalin, Andrey A.
AU - Dozmorov, Mikhail G.
AU - Kumar, Gaurav
AU - Swedish Schizophrenia Consortium
AU - Vladimirov, Vladimir I.
AU - Magnusson, Patrik K. E.
AU - Aberg, Karolina A.
PY - 2016
Y1 - 2016
N2 - 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 CpGSNPs 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 CpGSNPs 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.
AB - 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 CpGSNPs 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 CpGSNPs 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.
KW - DNA methylation
KW - MBD-seq
KW - methylome-wide association study
KW - postmortem brain samples
KW - PSYCHOSIS
KW - SNPs
UR - http://www.scopus.com/inward/record.url?scp=84979248318&partnerID=8YFLogxK
U2 - 10.1093/schbul/sbv182
DO - 10.1093/schbul/sbv182
M3 - Article
C2 - 26656881
AN - SCOPUS:84979248318
SN - 0586-7614
VL - 42
SP - 1018
EP - 1026
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 4
ER -