Leveraging genetic correlation structure to target discrete signaling mechanisms across metabolic tissues

Abstract

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively 1–4 . A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population 5–9 . Expanding on this intuition, we reasoned that parallel strategies could be leveraged to understand how individual genes mediate signaling across metabolic tissues through correlative analysis of genetic variation. Thus, genetics could aid in understanding cross-organ signaling by adopting a genecentric approach. Here, we surveyed gene-gene genetic correlation structure for ∼6.1×10^ 12 gene pairs across 18 metabolic tissues in 310 individuals where variation of genes such as FGF21, ADIPOQ, GCG and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both local signaling mechanisms (liver PCSK9) as well as genes encoding enzymes producing metabolites (adipose PNPLA2), where genetic correlation structure aligned with known roles for these critical metabolic pathways. Finally, we utilized this resource to suggest new functions for metabolic coordination between organs. For example, we prioritized key proteins for putative signaling between skeletal muscle and hippocampus, and further suggest colon as a central coordinator for systemic circadian clocks. We refer to this resource as G enetically- D erived C orrelations A cross Tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find genetic coregulation of genes, cell types, pathways and network architectures across metabolic organs.

Circadian rhythms in colonic function

“…Recent correlative analyses of genetic variation across multiple organs and cell types identify the colon as a major cross organ regulator of gene expression, showing more genes under rhythmic circadian control than any other organ analysed ( Zhou et al, 2023 ). Most clock genes have been identified in the healthy colon and may be controlled by non-SCN peripheral influences.…”