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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

TitleLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
Publication TypeJournal Article
Year of Publication2015
AuthorsWessel J, Chu AY, Willems SM, et al.
Secondary AuthorsGoodarzi MO
Corporate AuthorsEPIC-InterAct Consortium
JournalNat Commun
Volume6
Pagination5897
Date Published2015 Jan 29
ISSN2041-1723
KeywordsAfrican Continental Ancestry Group, Blood Glucose, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Exome, Fasting, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor, Glucose-6-Phosphatase, Humans, Insulin, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide
Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

DOI10.1038/ncomms6897
Alternate JournalNat Commun
PubMed ID25631608
PubMed Central IDPMC4311266
Grant ListR01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100037C / HL / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
R01 HL071025 / HL / NHLBI NIH HHS / United States
R01-HL-088215 / HL / NHLBI NIH HHS / United States
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RC2 HL102419 / HL / NHLBI NIH HHS / United States
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HHSN268201100009I / HL / NHLBI NIH HHS / United States
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N01-HC-95162 / HC / NHLBI NIH HHS / United States
DK093757 / DK / NIDDK NIH HHS / United States
HHSN268201300026C / HL / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
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HG007112 / HG / NHGRI NIH HHS / United States
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UL1 TR000150 / TR / NCATS NIH HHS / United States
MC_UP_A100_1003 / / Medical Research Council / United Kingdom
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UL1 RR025005 / RR / NCRR NIH HHS / United States
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095515 / / Wellcome Trust / United Kingdom
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