Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization

Area of Science:

• Genetics
• Metabolic Diseases
• Biomarkers

Background:

• Genome-wide association studies (GWAS) have identified numerous genetic loci associated with glycemic traits.
• Linking these loci to specific genes and biological pathways remains a significant challenge in understanding glucose homeostasis.

Purpose of the Study:

• To identify coding variant associations that pinpoint effector genes at GWAS loci for glycemic traits.
• To explore novel and established associations using exome-array data and pathway analyses.

Main Methods:

• Performed meta-analyses of exome-array studies for glycated hemoglobin (HbA1c), fasting glucose (FG), fasting insulin (FI), and 2-hour post-oral glucose challenge (2hGlu).
• Conducted single-variant and gene-based association analyses.
• Utilized network and pathway analyses to explore biological mechanisms.

Main Results:

• Identified coding variant associations at over 60 genes, aiding in the nomination of effector genes.
• Discovered pathways related to insulin secretion, zinc transport, and fatty acid metabolism.
• Found significant enrichment of HbA1c associations in blood cell biology pathways.

Conclusions:

• Provided novel genetic associations for glycemic traits and highlighted key regulatory pathways.
• Made exome-array summary statistics publicly available to facilitate further research and discovery in glycemic regulation.