Characterizing common and rare variations in non-traditional glycemic biomarkers using multivariate approaches on...

Glycated hemoglobin, fasting glucose, glycated albumin, and fructosamine are biomarkers that reflect different aspects of the glycemic process. Genetic studies of these glycemic biomarkers can shed light on unknown aspects of type 2 diabetes genetics and biology. While there exists several GWAS of glycated hemoglobin and fasting glucose, very few GWAS have focused on glycated albumin or fructosamine. We performed a multi-phenotype GWAS of glycated albumin and fructosamine from 7,395 White and 2,016 Black participants in the Atherosclerosis Risk in Communities (ARIC) study on the common variants from genotyped/imputed data. We found 2 genome-wide significant loci, one mapping to known type 2 diabetes gene (ARAP1/STARD10, p = 2.8 × 10^-8) and another mapping to a novel gene (UGT1A, p = 1.4 × 10^-8) using multi-omics gene mapping strategies in diabetes-relevant tissues. We identified additional loci that were ancestry-specific (e.g., PRKCA from African ancestry individuals, p = 1.7 × 10^-8) and sex-specific (TEX29 locus in males only, p = 3.0 × 10^-8). Further, we implemented multi-phenotype gene-burden tests on whole-exome sequence data from 6,590 White and 2,309 Black ARIC participants. Eleven genes across different rare variant aggregation strategies were exome-wide significant only in multi-ancestry analysis. Four out of 11 genes had notable enrichment of rare predicted loss of function variants in African ancestry participants despite smaller sample size. Overall, 8 out of 15 loci/genes were implicated to influence these biomarkers via glycemic pathways. This study illustrates improved locus discovery and potential effector gene discovery by leveraging joint patterns of related biomarkers across entire allele frequency spectrum in multi-ancestry analyses. Most of the loci/genes we identified have not been previously implicated in studies of type 2 diabetes, and future investigation of the loci/genes potentially acting through glycemic pathways may help us better understand risk of developing type 2 diabetes.