A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Area of Science:

• Genomics
• Metabolic Disease Research
• Molecular Biology

Background:

• Genome-wide association studies (GWAS) have identified over 200 genomic loci associated with metabolic disease (MD).
• Loss of insulin sensitivity (IS) is a critical factor in MD development.
• Understanding the genomic underpinnings of IS is crucial for unraveling MD genetics.

Purpose of the Study:

• To identify a robust transcriptome related to insulin sensitivity (IS) in human skeletal muscle.
• To explore the connection between the IS transcriptome and the genomic structure of metabolic disease (MD).
• To investigate the role of coding and non-coding RNAs in metabolic regulation.

Main Methods:

• Analysis of 1,012 human skeletal muscle samples with detailed physiological data.
• Quantification of over 18,000 coding and 15,000 non-coding RNAs (ncRNAs).
• Identification of fasting IS-related genes (CORE-IS) and their association with GWAS MD loci and clinical treatments.

Main Results:

• Identified 332 fasting IS-related genes (CORE-IS), with over 200 having known roles in insulin/metabolism or located at GWAS MD loci.
• More than 50% of CORE-IS genes responded to clinical treatment, with 16 genes quantitatively tracking IS changes across studies.
• Discovered an ncRNA network positively related to IS, interacting with viral response RNAs, and observed reduced amino acid catabolic gene expression.

Conclusions:

• Combining physiological phenotyping with RNA profiling effectively identifies molecular networks relevant to human metabolic disease.
• The identified CORE-IS genes and ncRNA networks offer insights into the genetic and biochemical basis of metabolic disease.
• This approach provides a foundation for understanding the genomic structure of metabolic disease and potential therapeutic targets.