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Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation
Author summary Genetic variation can drive alterations in gene expression levels and chromatin accessibility, the latter of which defines gene regulatory elements genome-wide. The same genetic variants may associate with both molecular events, and these may be connected within the same causal path: a variant that reduces promoter region chromatin accessibility, potentially by affecting transcription factor binding, may lead to reduced expression of that gene. Moreover, these causal regulatory paths can differ between tissues depending on functions and cellular activity specific to each tissue. We identify cross-tissue and tissue-selective genetic regulators of gene expression and chromatin accessibility in liver, lung, and kidney tissues using a panel of genetically diverse inbred mouse strains. Further, we identify a number of candidate causal mediators of the genetic regulation of gene expression, including a zinc finger protein that helps silence the Akr1e1 gene. Our analyses are consistent with chromatin accessibility playing a role in the regulation of transcription. Our study demonstrates the power of genetically diverse, multi-parental mouse populations, such as the Collaborative Cross, for large-scale studies of genetic drivers of gene regulation that underlie complex phenotypes, as well as identifying causal intermediates that drive variable activity of specific genes and pathways.
