Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci
Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWASs) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wid...
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| creator | Carnes, Megan Ulmer Quach, Bryan C Zhou, Linran Han, Shizhong Tao, Ran Mandal, Meisha Deep-Soboslay, Amy Marks, Jesse A Page, Grier P Maher, Brion S Jaffe, Andrew E Won, Hyejung Bierut, Laura J Hyde, Thomas M Kleinman, Joel E Johnson, Eric O Hancock, Dana B |
| description | Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWASs) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wide genotype, DNA methylation, and RNA sequencing data in postmortem human nucleus accumbens (NAc) to identify cis-methylation/expression quantitative trait loci (meQTLs/eQTLs), investigate variant-by-cigarette smoking interactions across the genome, and overlay QTL evidence at smoking GWAS-identified loci to evaluate their regulatory potential. Active smokers (N = 52) and nonsmokers (N = 171) were defined based on cotinine biomarker levels and next-of-kin reporting. We simultaneously tested variant and variant-by-smoking interaction effects on methylation and expression, separately, adjusting for biological and technical covariates and correcting for multiple testing using a two-stage procedure. We found >2 million significant meQTL variants (p |
| doi_str_mv | 10.1038/s41386-024-01885-4 |
| format | Article |
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< 0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects, and five meQTLs, mapping to NUDT12, FAM53B, RNF39, and ADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTL variants for 958 unique eGenes (p
< 0.05) and no smoking interactions. Colocalization analyses identified loci with smoking-associated GWAS variants that overlapped meQTLs/eQTLs, suggesting that these heritable factors may influence smoking behaviors through functional effects on methylation/expression. One locus containing MUSTN1 and ITIH4 colocalized across all data types (GWAS, meQTL, and eQTL). In this first genome-wide meQTL map in the human NAc, the enriched overlap with smoking GWAS-identified genetic loci provides evidence that gene regulation in the brain helps explain the neurobiology of smoking behaviors.</description><identifier>ISSN: 0893-133X</identifier><identifier>ISSN: 1740-634X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1038/s41386-024-01885-4</identifier><identifier>PMID: 38830989</identifier><language>eng</language><publisher>England: Springer International Publishing</publisher><ispartof>Neuropsychopharmacology (New York, N.Y.), 2024-06, Vol.49 (11), p.1749-1757</ispartof><rights>2024. The Author(s).</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c284t-3c8535f1a8bfce14b844bb651d98c488a39bcc69e9c94b2e133eb7318541bf5a3</cites><orcidid>0000-0003-2582-3786 ; 0000-0002-9952-4810 ; 0000-0003-3651-0566 ; 0000-0002-8870-1949 ; 0000-0002-4210-6052 ; 0000-0002-1094-3104 ; 0000-0002-8746-3037 ; 0000-0003-2240-3604</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38830989$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carnes, Megan Ulmer</creatorcontrib><creatorcontrib>Quach, Bryan C</creatorcontrib><creatorcontrib>Zhou, Linran</creatorcontrib><creatorcontrib>Han, Shizhong</creatorcontrib><creatorcontrib>Tao, Ran</creatorcontrib><creatorcontrib>Mandal, Meisha</creatorcontrib><creatorcontrib>Deep-Soboslay, Amy</creatorcontrib><creatorcontrib>Marks, Jesse A</creatorcontrib><creatorcontrib>Page, Grier P</creatorcontrib><creatorcontrib>Maher, Brion S</creatorcontrib><creatorcontrib>Jaffe, Andrew E</creatorcontrib><creatorcontrib>Won, Hyejung</creatorcontrib><creatorcontrib>Bierut, Laura J</creatorcontrib><creatorcontrib>Hyde, Thomas M</creatorcontrib><creatorcontrib>Kleinman, Joel E</creatorcontrib><creatorcontrib>Johnson, Eric O</creatorcontrib><creatorcontrib>Hancock, Dana B</creatorcontrib><title>Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci</title><title>Neuropsychopharmacology (New York, N.Y.)</title><addtitle>Neuropsychopharmacology</addtitle><description>Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWASs) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wide genotype, DNA methylation, and RNA sequencing data in postmortem human nucleus accumbens (NAc) to identify cis-methylation/expression quantitative trait loci (meQTLs/eQTLs), investigate variant-by-cigarette smoking interactions across the genome, and overlay QTL evidence at smoking GWAS-identified loci to evaluate their regulatory potential. Active smokers (N = 52) and nonsmokers (N = 171) were defined based on cotinine biomarker levels and next-of-kin reporting. We simultaneously tested variant and variant-by-smoking interaction effects on methylation and expression, separately, adjusting for biological and technical covariates and correcting for multiple testing using a two-stage procedure. We found >2 million significant meQTL variants (p
< 0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects, and five meQTLs, mapping to NUDT12, FAM53B, RNF39, and ADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTL variants for 958 unique eGenes (p
< 0.05) and no smoking interactions. Colocalization analyses identified loci with smoking-associated GWAS variants that overlapped meQTLs/eQTLs, suggesting that these heritable factors may influence smoking behaviors through functional effects on methylation/expression. One locus containing MUSTN1 and ITIH4 colocalized across all data types (GWAS, meQTL, and eQTL). In this first genome-wide meQTL map in the human NAc, the enriched overlap with smoking GWAS-identified genetic loci provides evidence that gene regulation in the brain helps explain the neurobiology of smoking behaviors.</description><issn>0893-133X</issn><issn>1740-634X</issn><issn>1740-634X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpVkU1PxCAURYnR6PjxB1yYLt2gUGj7WBlj_EomMUZN3BFg6AzawggdR_31VjsaXRHCvYf3chDap-SIEgbHiVMGJSY5x4QCFJivoRGtOMEl44_raERAMEwZe9xC2yk9EUKLqoRNtMUAGBEgRmh514Zn56fY-TrE1k6y1naz90Z1LvhM-Ulm3-bRpvR1vb0fp8z5bLZolc90VG6ImNAEoxr3MbSWrptlacVVKQXjVNeTp9bbzpmsD7tdtFGrJtm91bmDHi7O78-u8Pjm8vrsdIxNDrzDzEDBipoq0LWxlGvgXOuyoBMBhgMoJrQxpbDCCK5z2y9rdcUoFJzqulBsB50M3PlC99sZ67uoGjmPrlXxXQbl5P8X72ZyGl4lpUyIvKp6wuGKEMPLwqZOti4Z2zTK27BIkpGSF0DyXPTRfIiaGFKKtv79hxL5pUwOymSvTH4rk7wvHfyd8Lfy44h9Ai6Clio</recordid><startdate>20240604</startdate><enddate>20240604</enddate><creator>Carnes, Megan Ulmer</creator><creator>Quach, Bryan C</creator><creator>Zhou, Linran</creator><creator>Han, Shizhong</creator><creator>Tao, Ran</creator><creator>Mandal, Meisha</creator><creator>Deep-Soboslay, Amy</creator><creator>Marks, Jesse A</creator><creator>Page, Grier P</creator><creator>Maher, Brion S</creator><creator>Jaffe, Andrew E</creator><creator>Won, Hyejung</creator><creator>Bierut, Laura J</creator><creator>Hyde, Thomas M</creator><creator>Kleinman, Joel E</creator><creator>Johnson, Eric O</creator><creator>Hancock, Dana B</creator><general>Springer International Publishing</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2582-3786</orcidid><orcidid>https://orcid.org/0000-0002-9952-4810</orcidid><orcidid>https://orcid.org/0000-0003-3651-0566</orcidid><orcidid>https://orcid.org/0000-0002-8870-1949</orcidid><orcidid>https://orcid.org/0000-0002-4210-6052</orcidid><orcidid>https://orcid.org/0000-0002-1094-3104</orcidid><orcidid>https://orcid.org/0000-0002-8746-3037</orcidid><orcidid>https://orcid.org/0000-0003-2240-3604</orcidid></search><sort><creationdate>20240604</creationdate><title>Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci</title><author>Carnes, Megan Ulmer ; Quach, Bryan C ; Zhou, Linran ; Han, Shizhong ; Tao, Ran ; Mandal, Meisha ; Deep-Soboslay, Amy ; Marks, Jesse A ; Page, Grier P ; Maher, Brion S ; Jaffe, Andrew E ; Won, Hyejung ; Bierut, Laura J ; Hyde, Thomas M ; Kleinman, Joel E ; Johnson, Eric O ; Hancock, Dana B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c284t-3c8535f1a8bfce14b844bb651d98c488a39bcc69e9c94b2e133eb7318541bf5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carnes, Megan Ulmer</creatorcontrib><creatorcontrib>Quach, Bryan C</creatorcontrib><creatorcontrib>Zhou, Linran</creatorcontrib><creatorcontrib>Han, Shizhong</creatorcontrib><creatorcontrib>Tao, Ran</creatorcontrib><creatorcontrib>Mandal, Meisha</creatorcontrib><creatorcontrib>Deep-Soboslay, Amy</creatorcontrib><creatorcontrib>Marks, Jesse A</creatorcontrib><creatorcontrib>Page, Grier P</creatorcontrib><creatorcontrib>Maher, Brion S</creatorcontrib><creatorcontrib>Jaffe, Andrew E</creatorcontrib><creatorcontrib>Won, Hyejung</creatorcontrib><creatorcontrib>Bierut, Laura J</creatorcontrib><creatorcontrib>Hyde, Thomas M</creatorcontrib><creatorcontrib>Kleinman, Joel E</creatorcontrib><creatorcontrib>Johnson, Eric O</creatorcontrib><creatorcontrib>Hancock, Dana B</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carnes, Megan Ulmer</au><au>Quach, Bryan C</au><au>Zhou, Linran</au><au>Han, Shizhong</au><au>Tao, Ran</au><au>Mandal, Meisha</au><au>Deep-Soboslay, Amy</au><au>Marks, Jesse A</au><au>Page, Grier P</au><au>Maher, Brion S</au><au>Jaffe, Andrew E</au><au>Won, Hyejung</au><au>Bierut, Laura J</au><au>Hyde, Thomas M</au><au>Kleinman, Joel E</au><au>Johnson, Eric O</au><au>Hancock, Dana B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci</atitle><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle><addtitle>Neuropsychopharmacology</addtitle><date>2024-06-04</date><risdate>2024</risdate><volume>49</volume><issue>11</issue><spage>1749</spage><epage>1757</epage><pages>1749-1757</pages><issn>0893-133X</issn><issn>1740-634X</issn><eissn>1740-634X</eissn><abstract>Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWASs) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wide genotype, DNA methylation, and RNA sequencing data in postmortem human nucleus accumbens (NAc) to identify cis-methylation/expression quantitative trait loci (meQTLs/eQTLs), investigate variant-by-cigarette smoking interactions across the genome, and overlay QTL evidence at smoking GWAS-identified loci to evaluate their regulatory potential. Active smokers (N = 52) and nonsmokers (N = 171) were defined based on cotinine biomarker levels and next-of-kin reporting. We simultaneously tested variant and variant-by-smoking interaction effects on methylation and expression, separately, adjusting for biological and technical covariates and correcting for multiple testing using a two-stage procedure. We found >2 million significant meQTL variants (p
< 0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects, and five meQTLs, mapping to NUDT12, FAM53B, RNF39, and ADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTL variants for 958 unique eGenes (p
< 0.05) and no smoking interactions. Colocalization analyses identified loci with smoking-associated GWAS variants that overlapped meQTLs/eQTLs, suggesting that these heritable factors may influence smoking behaviors through functional effects on methylation/expression. One locus containing MUSTN1 and ITIH4 colocalized across all data types (GWAS, meQTL, and eQTL). In this first genome-wide meQTL map in the human NAc, the enriched overlap with smoking GWAS-identified genetic loci provides evidence that gene regulation in the brain helps explain the neurobiology of smoking behaviors.</abstract><cop>England</cop><pub>Springer International Publishing</pub><pmid>38830989</pmid><doi>10.1038/s41386-024-01885-4</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-2582-3786</orcidid><orcidid>https://orcid.org/0000-0002-9952-4810</orcidid><orcidid>https://orcid.org/0000-0003-3651-0566</orcidid><orcidid>https://orcid.org/0000-0002-8870-1949</orcidid><orcidid>https://orcid.org/0000-0002-4210-6052</orcidid><orcidid>https://orcid.org/0000-0002-1094-3104</orcidid><orcidid>https://orcid.org/0000-0002-8746-3037</orcidid><orcidid>https://orcid.org/0000-0003-2240-3604</orcidid><oa>free_for_read</oa></addata></record> |
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| title | Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci |
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