Common and ethnic-specific derangements in skeletal muscle transcriptome associated with obesity

Obesity is a common disease with a higher prevalence among African Americans. Obesity alters cellular function in many tissues, including skeletal muscle, and is a risk factor for many life-threatening diseases, including cardiovascular disease and diabetes. The similarities and differences in molecular mechanisms that may explain ethnic disparities in obesity between African and European ancestry individuals have not been studied.

In this study, data from transcriptome-wide analyses on skeletal muscle tissues from well-powered human cohorts were used to compare genes and biological pathways affected by obesity in European and African ancestry populations. Data on obesity-induced differentially expressed transcripts and GWAS-identified SNPs were integrated to prioritize target genes for obesity-associated genetic variants.

Linear regression analysis in the FUSION (European, N = 301) and AAGMEx (African American, N = 256) cohorts identified a total of 2569 body mass index (BMI)-associated transcripts (q < 0.05), of which 970 genes (at p < 0.05) are associated in both cohorts, and the majority showed the same direction of effect on BMI. Biological pathway analyses, including over-representation and gene-set enrichment analyses, identified enrichment of protein synthesis pathways (e.g., ribosomal function) and the ceramide signaling pathway in both cohorts among BMI-associated down- and up-regulated transcripts, respectively. A comparison using the IPA-tool suggested the activation of inflammation pathways only in Europeans with obesity. Interestingly, these analyses suggested repression of the mitochondrial oxidative phosphorylation pathway in Europeans but showed its activation in African Americans. Integration of SNP-to-Gene analyses-predicted target genes for obesity-associated genetic variants (GWAS-identified SNPs) and BMI-associated transcripts suggested that these SNPs might cause obesity by altering the expression of 316 critical target genes (e.g., GRB14) in the muscle.

This study provides a replication of obesity-associated transcripts and biological pathways in skeletal muscle across ethnicities, but also identifies obesity-associated processes unique in either African or European ancestry populations.