Schizophrenia is associated with altered DNA methylation variance
Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation...
Gespeichert in:
| Veröffentlicht in: | Molecular psychiatry 2024-09 |
|---|---|
| Hauptverfasser: | , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | |
| container_start_page | |
| container_title | Molecular psychiatry |
| container_volume | |
| creator | Kiltschewskij, Dylan J Reay, William R Cairns, Murray J |
| description | Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR |
| doi_str_mv | 10.1038/s41380-024-02749-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3104538213</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3104538213</sourcerecordid><originalsourceid>FETCH-LOGICAL-c184t-49604bb5d4b40c24606890c5f86b3f313332efc6b69ff59089cb7de516f145533</originalsourceid><addsrcrecordid>eNo9kEtPAyEUhYnR2Fr9Ay7MLN2gMDwGlk19Jo0u1DUBBjKYeVSgmvrrndrq4ubem3vOyc0HwDlGVxgRcZ0oJgJBVNKxKiohOwBTTCsOGavE4TgTJiHFgk7ASUrvCG2P7BhMiCwrXDE8BfMX24TvYdVE1wddhFTolAYbdHZ18RVyU-g2uzguN0_zonO52bQ6h6EvPnUMurfuFBx53SZ3tu8z8HZ3-7p4gMvn-8fFfAnt-ECGVHJEjWE1NRTZknLEhUSWecEN8QQTQkrnLTdces8kEtKaqnYMc48pY4TMwOUudxWHj7VLWXUhWde2unfDOimCEWVElHgrLXdSG4eUovNqFUOn40ZhpLbo1A6dGtGpX3SKjaaLff7adK7-t_yxIj9DGmiP</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3104538213</pqid></control><display><type>article</type><title>Schizophrenia is associated with altered DNA methylation variance</title><source>SpringerLink Journals - AutoHoldings</source><creator>Kiltschewskij, Dylan J ; Reay, William R ; Cairns, Murray J</creator><creatorcontrib>Kiltschewskij, Dylan J ; Reay, William R ; Cairns, Murray J</creatorcontrib><description>Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n = 644) from additional cohorts and a non-psychiatric comparison group (n = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-024-02749-5</identifier><identifier>PMID: 39271751</identifier><language>eng</language><publisher>England</publisher><ispartof>Molecular psychiatry, 2024-09</ispartof><rights>2024. The Author(s).</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c184t-49604bb5d4b40c24606890c5f86b3f313332efc6b69ff59089cb7de516f145533</cites><orcidid>0000-0001-7689-2453 ; 0000-0003-2490-2538</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39271751$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kiltschewskij, Dylan J</creatorcontrib><creatorcontrib>Reay, William R</creatorcontrib><creatorcontrib>Cairns, Murray J</creatorcontrib><title>Schizophrenia is associated with altered DNA methylation variance</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><description>Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n = 644) from additional cohorts and a non-psychiatric comparison group (n = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.</description><issn>1359-4184</issn><issn>1476-5578</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNo9kEtPAyEUhYnR2Fr9Ay7MLN2gMDwGlk19Jo0u1DUBBjKYeVSgmvrrndrq4ubem3vOyc0HwDlGVxgRcZ0oJgJBVNKxKiohOwBTTCsOGavE4TgTJiHFgk7ASUrvCG2P7BhMiCwrXDE8BfMX24TvYdVE1wddhFTolAYbdHZ18RVyU-g2uzguN0_zonO52bQ6h6EvPnUMurfuFBx53SZ3tu8z8HZ3-7p4gMvn-8fFfAnt-ECGVHJEjWE1NRTZknLEhUSWecEN8QQTQkrnLTdces8kEtKaqnYMc48pY4TMwOUudxWHj7VLWXUhWde2unfDOimCEWVElHgrLXdSG4eUovNqFUOn40ZhpLbo1A6dGtGpX3SKjaaLff7adK7-t_yxIj9DGmiP</recordid><startdate>20240913</startdate><enddate>20240913</enddate><creator>Kiltschewskij, Dylan J</creator><creator>Reay, William R</creator><creator>Cairns, Murray J</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7689-2453</orcidid><orcidid>https://orcid.org/0000-0003-2490-2538</orcidid></search><sort><creationdate>20240913</creationdate><title>Schizophrenia is associated with altered DNA methylation variance</title><author>Kiltschewskij, Dylan J ; Reay, William R ; Cairns, Murray J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c184t-49604bb5d4b40c24606890c5f86b3f313332efc6b69ff59089cb7de516f145533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kiltschewskij, Dylan J</creatorcontrib><creatorcontrib>Reay, William R</creatorcontrib><creatorcontrib>Cairns, Murray J</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kiltschewskij, Dylan J</au><au>Reay, William R</au><au>Cairns, Murray J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Schizophrenia is associated with altered DNA methylation variance</atitle><jtitle>Molecular psychiatry</jtitle><addtitle>Mol Psychiatry</addtitle><date>2024-09-13</date><risdate>2024</risdate><issn>1359-4184</issn><issn>1476-5578</issn><eissn>1476-5578</eissn><abstract>Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n = 644) from additional cohorts and a non-psychiatric comparison group (n = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.</abstract><cop>England</cop><pmid>39271751</pmid><doi>10.1038/s41380-024-02749-5</doi><orcidid>https://orcid.org/0000-0001-7689-2453</orcidid><orcidid>https://orcid.org/0000-0003-2490-2538</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1359-4184 |
| ispartof | Molecular psychiatry, 2024-09 |
| issn | 1359-4184 1476-5578 1476-5578 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3104538213 |
| source | SpringerLink Journals - AutoHoldings |
| title | Schizophrenia is associated with altered DNA methylation variance |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T21%3A18%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Schizophrenia%20is%20associated%20with%20altered%20DNA%20methylation%20variance&rft.jtitle=Molecular%20psychiatry&rft.au=Kiltschewskij,%20Dylan%20J&rft.date=2024-09-13&rft.issn=1359-4184&rft.eissn=1476-5578&rft_id=info:doi/10.1038/s41380-024-02749-5&rft_dat=%3Cproquest_cross%3E3104538213%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3104538213&rft_id=info:pmid/39271751&rfr_iscdi=true |