Carver Kathryn, Clark Carolina, Zhong Yizhen, Yang Guang, Mishra Mrinal, Alarcon Cristina, Perera Minoli
Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611.
Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN.
bioRxiv. 2025 Jan 26:2025.01.23.634506. doi: 10.1101/2025.01.23.634506.
Methylation quantitative trait loci (meQTL) mapping can provide insight into the genetic architecture underlying the epigenome by identifying single-nucleotide polymorphisms (SNPs) associated with differential methylation at methylation sites (CpGs) across the genome. Given that the epigenetic architecture underlying differences in gene expression can vary across racial populations, performing epigenomic studies in African Americans is crucial for understanding the interplay between genetic variation, DNA methylation, and gene expression in this understudied group. By performing cis-meQTL mapping in African American hepatocytes, we identified 410,186 cis-meQTLs associated with methylation at 24,425 CpGs in the liver. Through colocalization analysis, we found that 18,206 of these meQTLs are also colocalized with known liver eQTLs. Additionally, we found that using African American eQTL data results in an increased ability to detect additional colocalized variants that exhibit strong differences in allele frequency between people of European and African ancestry. Furthermore, the presence of smaller linkage disequilibrium blocks in African Americans allows us to identify narrower genomic regions of potentially causal variants compared to when data from Europeans is used. Importantly, these colocalized SNPs are significantly enriched for genetic associations with lipid and inflammatory traits in the GWAS catalog, suggesting that DNA methylation may contribute to the etiologies of these diseases. Furthermore, while it is generally presumed that the genetic regulation of DNA methylation is shared between blood and liver, we found that only 5.4% of African American liver meQTLs colocalize with blood meQTLs. Overall, our results reveal that studying African American populations results in the identification of additional genetic and epigenetic factors that may regulate gene expression in the liver, thereby expanding our understanding of gene regulation in African Americans.
甲基化数量性状基因座（meQTL）定位可通过识别与全基因组甲基化位点（CpG）处差异甲基化相关的单核苷酸多态性（SNP），深入了解表观基因组的遗传结构。鉴于基因表达差异背后的表观遗传结构可能因种族群体而异，对非裔美国人进行表观基因组研究对于理解这一研究不足群体中基因变异、DNA甲基化和基因表达之间的相互作用至关重要。通过在非裔美国人肝细胞中进行顺式meQTL定位，我们在肝脏中鉴定出410,186个与24,425个CpG甲基化相关的顺式meQTL。通过共定位分析，我们发现其中18,206个meQTL也与已知的肝脏表达数量性状基因座（eQTL）共定位。此外，我们发现使用非裔美国人的eQTL数据能够增强检测其他共定位变异的能力，这些变异在欧洲和非洲血统人群的等位基因频率上表现出强烈差异。此外，与使用欧洲人的数据相比，非裔美国人中较小的连锁不平衡块使我们能够识别潜在因果变异的更窄基因组区域。重要的是，这些共定位的SNP在全基因组关联研究（GWAS）目录中与脂质和炎症性状的遗传关联显著富集，这表明DNA甲基化可能有助于这些疾病的病因。此外，虽然通常认为DNA甲基化的遗传调控在血液和肝脏之间是共享的，但我们发现只有5.4%的非裔美国人肝脏meQTL与血液meQTL共定位。总体而言，我们的结果表明，研究非裔美国人种群可识别出可能调节肝脏基因表达的其他遗传和表观遗传因素，从而扩展我们对非裔美国人基因调控的理解。
