Genome-wide characterization of circulating metabolic biomarkers

Area of Science:

• Human genetics
• Metabolomics
• Systems biology

Background:

• Genome-wide association studies (GWAS) using high-throughput metabolomics have advanced understanding of human metabolism.
• Genetic determinants of metabolism are crucial for understanding biological mechanisms and complex diseases.

Purpose of the Study:

• To conduct a genome-wide association study for 233 circulating metabolic traits.
• To identify genetic loci and probable causal genes influencing human metabolism.
• To explore the translational utility of metabolic profiling data.

Main Methods:

• Genome-wide association study (GWAS) of 233 metabolic traits.
• Nuclear magnetic resonance (NMR) spectroscopy for metabolic trait quantification.
• Analysis of up to 136,016 participants from 33 cohorts.
• Manual curation to assign probable causal genes.
• Metabolic profiling of lipoprotein- and lipid-associated variants.
• Mendelian randomization analysis.

Main Results:

• Identification of over 400 independent genetic loci associated with metabolic traits.
• Assignment of probable causal genes for two-thirds of identified loci.
• Characterization of how known and novel loci affect lipoprotein metabolism.
• Demonstration of metabolic associations with intrahepatic cholestasis of pregnancy.
• Observation of substantial genetic pleiotropy across metabolic pathways.
• Revealed a putative causal relationship between acetone and hypertension.

Conclusions:

• The study provides a foundational resource for investigating the role of metabolism in diverse diseases.
• Detailed metabolic profiling offers insights into genetic influences on lipoprotein and lipid metabolism.
• Genetic pleiotropy highlights interconnectedness of metabolic pathways.
• Findings underscore the importance of careful methodology in genetic association studies.