New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Am J Hum Genet. 2024 Jan 4;111(1):133-149. doi: 10.1016/j.ajhg.2023.11.013.
Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.
组织的分子数量性状基因座（QTLs）一直是解释与疾病相关变异的起点，而特定于上下文的 QTL 对疾病具有特别重要的意义。在这里，我们展示了在来自不同祖先个体的血液的多组学、纵向数据中，针对细胞类型、年龄和其他表型变量的互作 QTL（iQTL）作图的结果。通过对基因型和估计的细胞类型比例之间的相互作用进行建模，我们证明细胞类型 iQTL 可以被视为细胞类型特异性 QTL 效应的代理，特别是对于组织中最丰富的细胞类型。然而，对年龄 iQTL 的解释需要谨慎，因为年龄对基因型和分子表型关联的调节作用可能是由细胞类型组成的变化介导的。最后，我们表明细胞类型 iQTL 有助于与疾病的细胞类型特异性富集，结合其他功能数据，可以指导未来的功能研究。总的来说，这项研究强调了使用 iQTL 来深入了解调节效应的上下文特异性。
