美国密歇根大学 Laura J. Scott等合作团队通过脂肪组织eQTL元分析，突出了等位基因异质性在基因表达调控和心脏代谢特征中的作用。这一研究成果于2025年1月2日发表在国际顶尖学术期刊《自然—遗传学》上。

据介绍，为了阐明复杂性状的组织生物学和病因学，需要完整地描述基因表达的遗传效应。

在本研究中，小组分析了2,344个皮下脂肪组织样本，并在18,476个基因中鉴定了34,774个条件不同表达数量性状位点（eQTL）信号。超过一半的eQTL基因表现出至少两个eQTL信号。与原代eQTL信号相比，非原代eQTL信号具有较小的效应量、较小的等位基因频率和较少的启动子富集。

它们对应的基因具有更高的遗传性和对功能丧失的更高耐受性。与28个心脏代谢性状的全基因组关联研究（GWAS）信号，共定位的eQTL鉴定出1835个基因。非初级eQTL信号的加入，使共定位GWAS-eQTL信号的发现增加了46%。

此外，21个GWAS-eQTL共定位≥2个的基因，在GWAS性状中表现出介导基因剂量效应。因此，扩展的eQTL鉴定揭示了复杂性状的更多机制，并提高了对基因表达调控复杂性的理解。

附：英文原文

Title: Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits

Author: 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, Pivi, Tuomilehto, Jaakko, Collins, Francis S., Boehnke, Michael, Love, Michael I., Koistinen, Heikki A., Laakso, Markku, Mohlke, Karen L., Small, Kerrin S., Scott, Laura J.

Issue&Volume: 2025-01-02

Abstract: 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.

DOI: 10.1038/s41588-024-01982-6

Source: https://www.nature.com/articles/s41588-024-01982-6