Transcriptional regulatory mechanisms in adipose and muscle tissue associate with composite gluco-metabolic phenotypes

OBJECTIVE: Tissue-specific gene expression is associated with individual metabolic measures. However, these measures may not reflect the true but latent underlying biological phenotype. This study reports gene expression associations with multi-dimensional gluco-metabolic characterizations of obesity, glucose homeostasis, and lipid traits. METHODS: Factor analysis was computed using orthogonal rotation to construct composite phenotypes (CPs) from 23 traits in 256 non-diabetic African Americans. Genome-wide transcript expression data from adipose and muscle were tested for association with CPs, and expression quantitative trait loci (eQTL) were identified by association between cis-SNPs and gene expression. RESULTS: The factor analysis identified six CPs. The CPs 1 through 6 individually explained 34%, 12%, 9%, 8%, 6% and 5% of the variation in 23 gluco-metabolic traits studied. There were 3994 and 929 CP–associated transcripts identified in adipose and muscle, respectively; CP2 had the largest number of associated transcripts. Pathway analysis identified multiple canonical pathways from the CP-associated transcripts. In adipose and muscle, significant cis-eQTL were identified for 558 and 164 CP-associated transcripts (q-value <0.01), respectively. CONCLUSIONS: Adipose and muscle transcripts comprehensively define pathways involved in regulating gluco-metabolic disorders. Cis-eQTLs for CP-associated eGenes may act as primary causal determinants of gluco-metabolic phenotypes by regulating transcription of key genes.