Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.

Autor: Carnes MU; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina., Quach BC; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina., Zhou L; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina., Han S; Lieber Institute for Brain Development (LIBD), Baltimore, Maryland., Tao R; Lieber Institute for Brain Development (LIBD), Baltimore, Maryland., Mandal M; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina., Deep-Soboslay A; Lieber Institute for Brain Development (LIBD), Baltimore, Maryland., Marks JA; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina., Page GP; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina.; Fellow Program, RTI International, Research Triangle Park, North Carolina., Maher BS; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland., Jaffe AE; Lieber Institute for Brain Development (LIBD), Baltimore, Maryland., Won H; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Bierut LJ; Department of Psychiatry, Washington University in St. Louis, Missouri., Hyde TM; Lieber Institute for Brain Development (LIBD), Baltimore, Maryland.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.; Department of Neurology, Johns Hopkins University, Baltimore, Maryland., Kleinman JE; Lieber Institute for Brain Development (LIBD), Baltimore, Maryland., Johnson EO; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina.; Fellow Program, RTI International, Research Triangle Park, North Carolina., Hancock DB; Genomics and Translational Research Center, RTI International, Research Triangle Park, North Carolina.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Sep 18. Date of Electronic Publication: 2023 Sep 18.
DOI: 10.1101/2023.09.18.23295431
Abstrakt: Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWAS) 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 using a two-stage multiple testing approach with eigenMT and Bonferroni corrections. We found >2 million significant meQTL variants (p adj <0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects; five meQTLs, mapping to NUDT12 , FAM53B , RNF39 , and ADRA1B , showed a significant interaction with smoking. We found 57,683 significant eQTLs for 958 unique eGenes (p adj <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 MUSTIN1 and ITIH4 colocalized across all data types (GWAS + meQTL + 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.
Competing Interests: Conflict of Interest Megan Ulmer Carnes: None Bryan C. Quach: None Linran Zhou: None Shizhong Han: None Ran Tao: None Meisha Mandal: None Amy Deep-Soboslay: None Jesse A. Marks: None Grier P. Page: None Brion S. Maher: None Andrew E. Jaffe: AEJ is currently an employee and shareholder of Neumora Therapeutics, which is unrelated to the contents of this manuscript. Hyejung Won: None Laura J. Bierut: LBJ is listed as an inventor on U.S. Patent 8,080,371,”Markers for Addiction,” covering the use of specific genetic variants in determining the diagnosis, prognosis, and treatment of addiction. Thomas M. Hyde: None Joel E. Kleinman: JEK is a paid consultant for Merck as a member of a data monitoring committee. Eric O. Johnson: None Dana B. Hancock: None
Databáze: MEDLINE
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