Genetic analysis of blood molecular phenotypes reveals regulatory networks affecting complex traits: a DIRECT study

Abstract

Genetic variants identified by genome-wide association studies can contribute to disease risk by altering the production and abundance of mRNA, proteins and other molecules. However, the interplay between molecular intermediaries that define the pathway from genetic variation to disease is not well understood. Here, we evaluated the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3,029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant was associated with multiple molecular phenotypes over multiple genomic regions. We find varying proportions of shared genetic regulation across phenotypes, highest between expression and proteins (66.6%). We were able to recapitulate a substantial proportion of gene expression genetic regulation in a diverse set of 44 tissues, with a median of 88% shared associations for blood expression and 22.3% for plasma proteins. Finally, the genetic and molecular associations were represented in networks including 2,828 known GWAS variants. One sub-network shows the trans relationship between rs149007767 and RTEN, and identifies GRB10 and IKZF1 as candidates mediating genes. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants across different molecular phenotypes.

Advances and Utility of the Human Plasma Proteome

“…Eventually, studying the complexity and effects of combining many different genetic variants will present exciting opportunities for proteomics to inform about cellular mechanisms on a molecular level . This is exemplified by GWAS-anchored studies connecting multiomic signatures of mRNA expression and levels of circulating protein and metabolites …”

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

“…The human whole blood eQTL lookup was performed with use of data from the DIRECT consortium in a total of 3, 029 subjects at high risk of developing type 2 diabetes or with recently diagnosed type 2 diabetes ( 25 ). A detailed explanation of the eQTL analysis has previously been published ( 26 ), and summary statistics are available (DOI: 10.5281/zenodo.4475681 ).…”

A Bayesian model selection approach to mediation analysis

“…The latter is particularly important in genetic studies where chance co-localization of genetic effects can be misinterpreted as causal associations. Mediation in this context can be seen as a small scale, focused version of causal network analysis (also known as Bayesian networks [ 31 ]) with genetic anchors [ 32 – 34 ], and Bayesian methods for inferring such networks are typically highly computationally intensive [ 35 , 36 ]. By focusing on mediation and employing conjugate priors, we avoid costly sampling techniques for calculating posterior summaries.…”