Characterizing Common and Rare Variations in Nontraditional Glycemic Biomarkers Using Multivariate Approaches on Multiancestry ARIC Study

Genetic studies of nontraditional glycemic biomarkers, glycated albumin and fructosamine, can shed light on unknown aspects of type 2 diabetes genetics and biology. We performed a multiphenotype genome-wide association study of glycated albumin and fructosamine from 7,395 White and 2,016 Black participants in the Atherosclerosis Risk in Communities (ARIC) study on common variants from genotyped/imputed data. We discovered two genome-wide significant loci, one mapping to a known type 2 diabetes gene (ARAP1/STARD10) and another mapping to a novel region (UGT1A complex of genes), using multiomics gene-mapping strategies in diabetes-relevant tissues. We identified additional loci that were ancestry- and sex-specific (e.g., PRKCA in African ancestry, FCGRT in European ancestry, TEX29 in males). Further, we implemented multiphenotype gene-burden tests on whole-exome sequence data from 6,590 White and 2,309 Black ARIC participants. Ten variant sets annotated to genes across different variant aggregation strategies were exome-wide significant only in multiancestry analysis, of which CD1D, EGFL7/AGPAT2, and MIR126 had notable enrichment of rare predicted loss of function variants in African ancestry despite smaller sample sizes. Overall, 8 of 14 discovered loci and genes were implicated to influence these biomarkers via glycemic pathways, and most of them were not previously implicated in studies of type 2 diabetes. This study illustrates improved locus discovery and potential effector gene discovery by leveraging joint patterns of related biomarkers across the entire allele frequency spectrum in multiancestry analysis. Future investigation of the loci and genes potentially acting through glycemic pathways may help us better understand the risk of developing type 2 diabetes.

• Glycated albumin and fructosamine are biomarkers reflecting aspects of the glycemic process different from glycated hemoglobin or blood glucose levels. Thus, they can shed light on unknown aspects of type 2 diabetes genetics and biology.

• We leveraged array-based and exome sequence data on multiancestry individuals in the U.S. to discover yet-unidentified genes.

• We discovered 14 common variant loci and rare variant genes associated with glycated albumin and/or fructosamine, some of which have been implicated in type 2 diabetes. Locus-specific effects at common variants may vary by sex. Some loci and gene associations were unique to either European or African ancestry.