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

Kira A Perzel Mandell,Andrew E Jaffe,Stephen A Semick,Amanda J Price,William S Ulrich,Thomas M Hyde,Daniel R Weinberger,Nicholas J Eagles,Leonardo Collado-Torres,Joel E Kleinman,Richard Wilton,Shizhong Han,Alexander S Szalay,Ran Tao

doi:10.1038/s41467-021-25517-3

Abstract

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.

Highlights

DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction
In dorsolateral prefrontal cortex (DLPFC) we found 25,382 significant (FDR < 0.01, Supplementary Dataset 2) SNP–CpG pairs, representing 147 SNPs and 25,303 CpGs, showing that most Psychiatric Genomics Consortium (PGC) loci contain SNPs that associate with local DNA methylation levels
Within the subset of significant DLPFC methylation quantitative trait locus (meQTL), hippocampal meQTLs had an overall sharing of π1 = 0.97, indicating that our findings are very consistent between brain regions. These results indicated that meQTL effects, at least in the context of genome-wide association studies (GWAS) associations with schizophrenia, have much broader effects than traditionally considered, and much wider than the 20 kb window examined at the full genome level

Summary

Introduction

DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction. A major puzzle in the field of functional genomics is understanding the molecular effects of genetic risk loci and variants identified by genome-wide association studies (GWAS) for many common disorders and traits which do not involve coding sequences This is challenging in tissues like brain that are difficult to access or model, leaving little clarity into genetic mechanisms behind psychiatric disorders such as schizophrenia (SCZD). While CpH sites are generally unmethylated in somatic tissues, neurons in the human brain have uniquely high levels of CpHm27 By leveraging this technology, we have created the most extensive genomic meQTL map in human postmortem brain tissue to date, and use this information to fine-tune our understanding of the molecular mechanisms of genetic and epigenetic risk for schizophrenia

Methods

Results

Conclusion