Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.
Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2023 Feb 28;14(1):1132. doi: 10.1038/s41467-023-36638-2.
The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leverage spatiotemporal information on 966 RNA-seq cardiac samples and perform an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identify 2,578 eQTLs associated with a specific developmental stage-, tissue- and/or cell type. Colocalization between eQTL and GWAS signals of five cardiac traits identified variants with high posterior probabilities for being causal in 210 GWAS loci. Pulse pressure GWAS loci are enriched for colocalization with fetal- and smooth muscle- eQTLs; pulse rate with adult- and cardiac muscle- eQTLs; and atrial fibrillation with cardiac muscle- eQTLs. Fine mapping identifies 79 credible sets with five or fewer SNPs, of which 15 were associated with spatiotemporal eQTLs. Our study shows that many cardiac GWAS variants impact traits and disease in a developmental stage-, tissue- and/or cell type-specific fashion.
数千个心脏 GWAS 信号背后的因果变异和基因尚未确定。在这里，我们利用 966 个 RNA-seq 心脏样本的时空信息，并进行表达数量性状基因座 (eQTL) 分析，同时考虑 eGenes 和 eIsoforms 检测 eQTL。我们确定了 2578 个与特定发育阶段、组织和/或细胞类型相关的 eQTL。五个心脏特征的 eQTL 和 GWAS 信号的共定位确定了 210 个 GWAS 基因座中具有高因果后验概率的变异。脉搏压 GWAS 基因座与胎儿和平滑肌 eQTL 共定位富集；脉搏率与成人和心肌 eQTL 共定位；心房颤动与心肌 eQTL 共定位。精细映射确定了 79 个具有五个或更少 SNP 的可信集，其中 15 个与时空 eQTL 相关。我们的研究表明，许多心脏 GWAS 变体以发育阶段、组织和/或细胞类型特异性的方式影响特征和疾病。
