An interaction map of circulating metabolites, immune gene networks, and their genetic regulation

Abstract

BackgroundImmunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up.ResultsWe identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus.ConclusionsThis study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1279-y) contains supplementary material, which is available to authorized users.

Genetic association of molecular traits: A help to identify causative variants in complex diseases

“…To tackle this, trans ‐molQTLs are a first step forward to infer module networks. New methods are developed to integrate multiple molecular phenotypes . Human quantitative genetics is thus leaping into the area of systems biology …”

“…New methods are developed to integrate multiple molecular phenotypes. 29,72,91,147 Human quantitative genetics is thus leaping into the area of systems biology. 148…”

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…Their results suggest that MHC genotypes have a key role in shaping the TCR repertoire by determining the V gene usage profiles of each individual's TCR repertoire. Recently, also a SNP in class I between HLA‐C and MICA was identified as trans‐eQTL for CD79B which is a subunit of a B‐cell receptor complex for antigen binding …”

“…Recently, also a SNP in class I between HLA-C and MICA was identified as trans-eQTL for CD79B which is a subunit of a B-cell receptor complex for antigen binding. 31…”

Co-expression analysis reveals interpretable gene modules controlled bytrans-acting genetic variants

“…To reduce the number of tested phenotypes, co-expression analysis methods are sometimes used to aggregate individual genes to co-expressed modules capturing signalling pathways and cellular processes [5]. Such approaches have been successful in identifying trans-eQTLs in yeast [6] as well as various human tissues [7][8][9] and purified immune cells [10,11].…”