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

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posted on 09.11.2021, 17:53 by Fernando Riveros-Mckay, David Roberts, Emanuele Di Angelantonio, Bing Yu, Nicole Soranzo, John Danesh, Elizabeth Selvin, Adam S Butterworth, Inês Barroso
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 (Nmeta=29,685). We identified a novel association near GCK (rs3757840, betameta=0.0062, MAF=0.49, pmeta=3.66x10-08) and confirmed the association near RCN3 (rs113886122, betameta=0.0134, MAF=0.17, pmeta= 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.

Funding

Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust x British Heart Foundation RG/13/13/30194 RG/18/13/33946 SP/09/002 Chief Scientist Office of the Scottish Government x Consejo Nacional de Ciencia y Tecnología México x 489672 National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health x U.S. Department of Health and Human Services > National Institutes of Health > National Human Genome Research Institute U01HG004402 Department of Health > National Institute for Health Research National Institute for Health Research (NIHR) x U.S. Department of Health and Human Services > National Institutes of Health HHSN268200625226C UL1RR025005 NCI x NHGRI x NHLBI x K24 HL152440 R01DK089174 WT206194 NHS Blood and Transplant England x NIDA x NIH x NIHR x BTRU-2014-10024 NIMH x NINDS x Office of the Director of the National Institutes of Health x Public Health Agency U.S. Department of Energy > Office of Electricity Delivery and Energy Reliability > Research and Development UK Medical Research Council x MR/L003120/1 UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health x Wellcome Trust 206194 Welsh Government x

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