Characterizing common and rare variations in non-traditional glycemic biomarkers using multivariate approaches on multi-ancestry ARIC study

ABSTRACT (249 words)

Genetic studies of non-traditional glycemic biomarkers, glycated albumin and fructosamine, can shed light on unknown aspects of type 2 diabetes genetics and biology. 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 common variants from genotyped/imputed data. We discovered 2 genome-wide significant loci, one mapping to known type 2 diabetes gene (ARAP1/STARD10) and another mapping to a novel region (UGT1A complex of genes) using multi-omics 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 multi-phenotype 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 multi-ancestry 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 out 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 multi-ancestry analysis. Future investigation of the loci and genes potentially acting through glycemic pathways may help us better understand risk of developing type 2 diabetes.

ARTICLE HIGHLIGHTS (100 words)

· 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 multi-ancestry individuals in the US 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.