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

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.

SUBMITTER: Perzel Mandell KA

PROVIDER: S-EPMC8413445 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Perzel Mandell Kira A KA Eagles Nicholas J NJ Wilton Richard R Price Amanda J AJ Semick Stephen A SA Collado-Torres Leonardo L Ulrich William S WS Tao Ran R Han Shizhong S Szalay Alexander S AS Hyde Thomas M TM Kleinman Joel E JE Weinberger Daniel R DR Jaffe Andrew E AE

Nature communications 20210902 1

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). Th ...[more]

PMID: 34475392

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Project description:Background:The study of DNA methylation quantitative trait loci (meQTLs) helps dissect regulatory mechanisms underlying genetic associations of human diseases. In this study, we conducted the first genome-wide examination of genetic drivers of methylation variation in response to a triglyceride-lowering treatment with fenofibrate (response-meQTL) by using an efficient analytic approach. Methods:Subjects (n?=?429) from the GAW20 real data set with genotype and both pre- (visit 2) and post- (visit 4) fenofibrate treatment methylation measurements were included. Following the quality control steps of removing certain cytosine-phosphate-guanine (CpG) probes, the post-/premethylation changes (post/pre) were log transformed and the association was performed on 208,449 CpG sites. An additive linear mixed-effects model was used to test the association between each CpG probe and single nucleotide polymorphisms (SNPs) around ±1 Mb region, with age, sex, smoke, batch effect, and principal components included as covariates. Bonferroni correction was applied to define the significance threshold (p?<?5.6?×?10-?10, given a total of 89,217,303 tests). Finally, we integrated our response-meQTL (re-meQTL) findings with the published genome-wide association study (GWAS) catalog of human diseases/traits. Results:We identified 1087 SNPs as cis re-meQTLs associated with 610 CpG probes/sites located in 351 unique gene loci. Among these 1087 cis re-meQTL SNPs, 229 were unique and 6 were co-localized at 8 unique disease/trait loci reported in the GWAS catalog (enrichment p?=?1.51?×?10-?23). Specifically, a lipid SNP, rs10903129, located in intron regions of gene TMEM57, was a re-meQTL (p?=?3.12?×?10-?36) associated with the CpG probe cg09222892, which is in the upstream region of the gene RHCE, indicating a new target gene for rs10903129. In addition, we found that SNP rs12710728 has a suggestive association with cg17097782 (p?=?1.77?×?10-?4), and that this SNP is in high linkage disequilibrium (LD) (R2?>?0.8) with rs7443270, which was previously reported to be associated with fenofibrate response (p?=?5.00?×?10-?6). Conclusions:By using a novel analytic approach, we efficiently identified thousands of cis re-meQTLs that provide a unique resource for further characterizing functional roles and gene targets of the SNPs that are most responsive to fenofibrate treatment. Our efficient analytic approach can be extended to large response quantitative trait locus studies with large sample sizes and multiple time points data.

Project description:ObjectiveDeficits in neurocognitive function have been demonstrated in individuals with schizophrenia and in the unaffected family members of these individuals. Genetic studies of such complementary traits, along with traditional analyses of diagnosis, may help to elucidate the biological pathways underlying familial liability to schizophrenia and related disorders. The authors conducted a multiplex, multigenerational family study using a genome-wide screen for schizophrenia and related neurocognitive phenotypes.MethodParticipants were 1) 676 European American individuals from 43 families, ascertained through an individual with schizophrenia, and 2) 236 healthy comparison subjects. Participants were evaluated clinically and examined through the use of a computerized neurocognitive test battery that provided measures of accuracy and speed on the cognitive domains of abstraction and mental flexibility; attention; verbal, face, and spatial memory; language and reasoning; spatial and emotion processing; and sensorimotor dexterity. A genome-wide linkage screen was also performed. Healthy comparison subjects were included in order to obtain normative phenotypic data but were not genotyped.ResultsSignificant evidence for linkage of schizophrenia to chromosome 19q was observed. Analysis of cognitive traits revealed significant linkage to chromosome 5q for the domains of abstraction and mental flexibility. A variety of other neurocognitive traits also showed nominal evidence of linkage to the 5q region. Joint analyses with diagnosis suggested that this quantitative trait locus may also influence schizophrenia.ConclusionsAlthough chromosome 5 has been implicated in previous linkage studies of schizophrenia, the identification of the chromosome 19 quantitative trait locus is a novel finding. The identification of the chromosome 5 quantitative trait locus through linkage to neurocognitive phenotypes in the present study may inform functional hypotheses pertaining to how genotypes are connected to disease.

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

Publications

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

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