An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript

Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 US White and 2,712 US Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. Here we performed a GWAS on 20,731 European ancestry blood donors, and meta-analysed our results with previous data from US White participants from The Atherosclerosis Risk in Communities (ARIC) study (N_meta=29,685). We identified a novel association near GCK (rs3757840, beta_meta=0.0062, MAF=0.49, p_meta=3.66x10^-08) and confirmed the association near RCN3 (rs113886122, beta_meta=0.0134, MAF=0.17, p_meta= 5.71x10^-18). Co-localization analysis with whole blood eQTL data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2=7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (p>0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni corrected p<0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus.