Brotman Sarah M, El-Sayed Moustafa Julia S, Guan Li, Broadaway K Alaine, Wang Dongmeng, Jackson Anne U, Welch Ryan, Currin Kevin W, Tomlinson Max, Vadlamudi Swarooparani, Stringham Heather M, Roberts Amy L, Lakka Timo A, Oravilahti Anniina, Fernandes Silva Lilian, Narisu Narisu, Erdos Michael R, Yan Tingfen, Bonnycastle Lori L, Raulerson Chelsea K, Raza Yasrab, Yan Xinyu, Parker Stephen C J, Kuusisto Johanna, Pajukanta Päivi, Tuomilehto Jaakko, Collins Francis S, Boehnke Michael, Love Michael I, Koistinen Heikki A, Laakso Markku, Mohlke Karen L, Small Kerrin S, Scott Laura J
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Nat Genet. 2025 Jan;57(1):180-192. doi: 10.1038/s41588-024-01982-6. Epub 2025 Jan 2.
Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS-eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS-eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.
为了阐明组织生物学和复杂性状的病因，需要对基因表达的遗传效应进行全面表征。在本研究中，我们分析了2344份皮下脂肪组织样本，在18476个基因中鉴定出34774个条件性不同的表达定量性状位点（eQTL）信号。超过一半的eQTL基因表现出至少两个eQTL信号。与主要eQTL信号相比，非主要eQTL信号的效应大小更低、次要等位基因频率更低且启动子富集更少；它们对应于具有更高遗传力和更高功能丧失耐受性的基因。对28种心脏代谢性状的全基因组关联研究（GWAS）信号与eQTL进行共定位，确定了1835个基因。纳入非主要eQTL信号使共定位的GWAS-eQTL信号的发现增加了46%。此外，21个具有≥2个共定位GWAS-eQTL信号的基因对GWAS性状显示出介导基因剂量效应。因此，扩展的eQTL鉴定揭示了更多复杂性状背后的机制，并增进了对基因表达调控复杂性的理解。
