1. Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.
- Author
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Carnes MU, Quach BC, Zhou L, Han S, Tao R, Mandal M, Deep-Soboslay A, Marks JA, Page GP, Maher BS, Jaffe AE, Won H, Bierut LJ, Hyde TM, Kleinman JE, Johnson EO, and Hancock DB
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Nucleus Accumbens metabolism, Brain metabolism, Aged, Quantitative Trait Loci, DNA Methylation, Genome-Wide Association Study, Smoking genetics, Smoking metabolism
- 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
adj < 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 (padj < 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., (© 2024. The Author(s).)- Published
- 2024
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