Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.
Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.
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人脑中吸烟相关的甲基化和表达 QTL 以及与吸烟相关基因位点的共定位。
DOI：
10.1101/2023.09.18.23295431
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Johnson,Eric
中科院分区：
文献类型：
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作者：
Carnes,MeganUlmer;Quach,BryanC;Zhou,Linran;Han,Shizhong;Tao,Ran;Mandal,Meisha;Deep-Soboslay,Amy;Marks,JesseA;Page,GrierP;Maher,BrionS;Jaffe,AndrewE;Won,Hyejung;Bierut,LauraJ;Hyde,ThomasM;Kleinman,JoelE;Johnson,Eric
吸烟是可预防的发病和死亡的主要原因。吸烟是可遗传的，吸烟行为的全基因组关联研究（GWASs）已经确定了数百个重要的基因位点。大多数gwas鉴定的变异是非编码的，具有未知的神经生物学效应。我们利用死后人类伏隔核（NAc）的全基因组基因型、DNA甲基化和RNA测序数据，鉴定了基因座的甲基化/表达数量性状（meQTLs/eQTLs），研究了基因组中吸烟变异的相互作用，并在吸烟gwas鉴定的基因座上覆盖了QTL证据，以评估它们的调控潜力。根据可替宁生物标志物水平和近亲报告来定义活跃吸烟者（N= 52）和非吸烟者（N= 171）。我们同时分别测试了变异和吸烟变异对甲基化和表达的相互作用，调整了生物和技术协变量，并使用两阶段程序对多重测试进行了校正。我们发现了bb200万个显著的meQTL变异（padj< 0.05），对应41,695个独特的cpg。结果在很大程度上是由主效应驱动的，五个meqtl（定位于toNUDT12、FAM53B、RNF39和adra1b）显示出与吸烟的显著相互作用。我们发现57,683个显著的eQTL变异，958个独特的eGenes (padj< 0.05)，没有吸烟相互作用。共定位分析发现与吸烟相关的GWAS变异位点与meqtl / eqtl重叠，表明这些遗传因素可能通过甲基化/表达的功能影响吸烟行为。一个包含mustn1和ditih4的基因座横跨所有数据类型（GWAS、meQTL和eQTL）。在人类NAc的第一个全基因组meQTL图谱中，与吸烟gwas鉴定的遗传位点的丰富重叠提供了证据，表明大脑中的基因调控有助于解释吸烟行为的神经生物学。
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 identifycis-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 (padj< 0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects, and five meQTLs, mapping toNUDT12,FAM53B,RNF39, andADRA1B, 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 containingMUSTN1andITIH4colocalized 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.