Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk

• Published in: Nature communications Vol. 12; no. 1; pp. 5251 - 12
• Main Authors: Perzel Mandell, Kira A., Eagles, Nicholas J., Wilton, Richard, Price, Amanda J., Semick, Stephen A., Collado-Torres, Leonardo, Ulrich, William S., Tao, Ran, Han, Shizhong, Szalay, Alexander S., Hyde, Thomas M., Kleinman, Joel E., Weinberger, Daniel R., Jaffe, Andrew E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 45/23; 631/208/176/1988; 631/208/212/177; 631/208/480; 692/699/476/1799; Age Factors; Bisulfite; Brain; Brain - metabolism; Brain - pathology; CpG islands; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA Methylation; Epigenesis, Genetic; Epigenetics; Gene expression; Gene mapping; Gene sequencing; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomes; Genomics; Genotype; Genotype-environment interactions; Heritability; Humanities and Social Sciences; Humans; Mental disorders; multidisciplinary; Neuroplasticity; Plastic properties; Plasticity; Polymorphism, Single Nucleotide; Quantitative trait loci; Quantitative Trait Loci - genetics; Risk; Schizophrenia; Schizophrenia - genetics; Science; Science (multidisciplinary); Single-nucleotide polymorphism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25517-3

DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction. Using whole-genome bisulfite sequencing, we have surveyed DNAm in 344 samples of human postmortem brain tissue from neurotypical subjects and individuals with schizophrenia. We identify genetic influence on local methylation levels throughout the genome, both at CpG sites and CpH sites, with 86% of SNPs and 55% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting the genes and regions with which these loci are epigenetically associated. These findings can be used to better characterize schizophrenia GWAS-identified variants as epigenetic risk variants. Regions differentially methylated by schizophrenia risk-SNPs explain much of the heritability associated with risk loci, despite covering only a fraction of the genomic space. We provide a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain. The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.