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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.

TitleAn Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript.
Publication TypeJournal Article
Year of Publication2022
AuthorsRiveros-Mckay F, Roberts D, Di Angelantonio E, Yu B, Soranzo N, Danesh J, Selvin E, Butterworth AS, Barroso I
JournalDiabetes
Volume71
Issue2
Pagination359-364
Date Published2022 02 01
ISSN1939-327X
Abstract

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 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci 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.

DOI10.2337/db21-0320
Alternate JournalDiabetes
PubMed ID34753797
Grant ListK24 HL152440 / HL / NHLBI NIH HHS / United States
R01 DK089174 / DK / NIDDK NIH HHS / United States
BTRU-2014-10024 / DH_ / Department of Health / United Kingdom
206194 / WT_ / Wellcome Trust / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
SP/09/002 / BHF_ / British Heart Foundation / United Kingdom
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
RG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom
/ CSO_ / Chief Scientist Office / United Kingdom
HHSN268201700001I / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States