Dataset Information

Methylome-wide association study of different responses to risperidone in schizophrenia.

ABSTRACT: Background: Accumulating evidence shows that DNA methylation plays a role in antipsychotic response. However, the mechanisms by which DNA methylation changes are associated with antipsychotic responses remain largely unknown. Methods: We performed a methylome-wide association study (MWAS) to evaluate the association between DNA methylation and the response to risperidone in schizophrenia. Genomic DNA methylation patterns were assessed using the Agilent Human DNA Methylation Microarray. Results: We identified numerous differentially methylated positions (DMPs) and regions (DMRs) associated with antipsychotic response. CYP46A1, SPATS2, and ATP6V1E1 had the most significant DMPs, with p values of 2.50 × 10^-6, 3.53 × 10^-6, and 5.71 × 10^-6, respectively. The top-ranked DMR was located on chromosome 7, corresponding to the PTPRN2 gene with a Šidák-corrected p-value of 9.04 × 10^-13. Additionally, a significant enrichment of synaptic function and neurotransmitters was found in the differentially methylated genes after gene ontology and pathway analysis. Conclusion: The identified DMP- and DMR-overlapping genes associated with antipsychotic response are related to synaptic function and neurotransmitters. These findings may improve understanding of the mechanisms underlying antipsychotic response and guide the choice of antipsychotic in schizophrenia.

SUBMITTER: Du H

PROVIDER: S-EPMC9815458 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Methylome-wide association study of different responses to risperidone in schizophrenia.

Du Huihui H Ma Jingsong J Zhou Wei W Li Mo M Huai Cong C Shen Lu L Wu Hao H Zhao Xianglong X Zhang Na N Gao Songyin S Wang Qi Q He Lin L Wu Xuming X Qin Shengying S Zhao Mingzhe M

Frontiers in pharmacology 20221222

<b>Background:</b> Accumulating evidence shows that DNA methylation plays a role in antipsychotic response. However, the mechanisms by which DNA methylation changes are associated with antipsychotic responses remain largely unknown. <b>Methods:</b> We performed a methylome-wide association study (MWAS) to evaluate the association between DNA methylation and the response to risperidone in schizophrenia. Genomic DNA methylation patterns were assessed using the Agilent Human DNA Methylation Microar ...[more]

PMID: 36618913

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Project description:ImportanceEpigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve disease management.ObjectiveTo identify schizophrenia DNA methylation biomarkers in blood.Design, setting, and participantsThe sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG-binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case-control participants using targeted pyrosequencing of bisulfite-converted DNA.Main outcomes and measuresStatus of schizophrenia cases and controls.ResultsOur MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 × 10-10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia.Conclusions and relevanceTo our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management.

Project description:BackgroundDepression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown.MethodsWe investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm.ResultsWidespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10-8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10-30; depression to DNAm: pFDR ranged from 0.028 to 0.003).ConclusionsPRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.

Dataset Information

Methylome-wide association study of different responses to risperidone in schizophrenia.

Publications

Methylome-wide association study of different responses to risperidone in schizophrenia.

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