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Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.

TitleGenome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.
Publication TypeJournal Article
Year of Publication2018
AuthorsKeaton JM, Gao C, Guan M, Hellwege JN, Palmer ND, Pankow JS, Fornage M, Wilson JG, Correa A, Rasmussen-Torvik LJ, Rotter JI, Chen Y-DI, Taylor KD, Rich SS, Wagenknecht LE, Freedman BI, C Y Ng M
Secondary AuthorsBowden DW
JournalGenet Epidemiol
Volume42
Issue6
Pagination559-570
Date Published2018 Sep
ISSN1098-2272
KeywordsAdaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Body Mass Index, Case-Control Studies, Diabetes Mellitus, Type 2, Epistasis, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin, Insulin Secretion, Male, Middle Aged, Models, Genetic, Polymorphism, Single Nucleotide, Receptor, Melatonin, MT2
Abstract

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (PĀ 

DOI10.1002/gepi.22126
Alternate JournalGenet Epidemiol
PubMed ID29691896
PubMed Central IDPMC6160319
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201300049C / / JHS / International
N01 HC095160 / HC / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
U01-HG04424 / / GENEVA / International
HHSN268201300026C / HL / NHLBI NIH HHS / United States
N01 HC095159 / HC / NHLBI NIH HHS / United States
N01-HC-95160 / / MESA / International
N01-HC-95163 / / MESA / International
N01 HC095167 / HC / NHLBI NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
R01 DK070941 / DK / NIDDK NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
HHSN268200900041C / / Johns Hopkins University School of Medicine / International
HHSN268201100005G / HL / NHLBI NIH HHS / United States
U01 DK105556 / DK / NIDDK NIH HHS / United States
UL1-TR-000040 / / MESA / International
HHSN268201100008I / HL / NHLBI NIH HHS / United States
N01 HC095164 / HC / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
N01 HC095169 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
DK063491 / / MESA / International
N01HC95169 / HL / NHLBI NIH HHS / United States
N01 HC095166 / HC / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268201300048C / HL / NHLBI NIH HHS / United States
N01-HC-95162 / / MESA / International
HHSN268201300050C / / JHS / International
U01 HG004402 / HG / NHGRI NIH HHS / United States
U01 HG004424 / HG / NHGRI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
HHSN268201300025C / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
N01-HC-95166 / / MESA / International
N01HC95162 / HL / NHLBI NIH HHS / United States
N01-HC-95165 / / MESA / International
N01HC95168 / HL / NHLBI NIH HHS / United States
R01 DK087914 / DK / NIDDK NIH HHS / United States
R01-HL-56266 / / GF / International
U01 HG004729 / HG / NHGRI NIH HHS / United States
HHSC268200782096C / / GF / International
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201300048C / / JHS / International
HHSN268201300027C / HL / NHLBI NIH HHS / United States
K99 DK081350 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
N01-HC-95168 / / MESA / International
HHSN268201300049C / HL / NHLBI NIH HHS / United States
N01 HC095163 / HC / NHLBI NIH HHS / United States
R01 DK066358 / DK / NIDDK NIH HHS / United States
R01-DK-087914 / / GF / International
U01-HG004446 / / GENEVA / International
HHSN268200900041C / HL / NHLBI NIH HHS / United States
N01 HC095165 / HC / NHLBI NIH HHS / United States
HHSN268201300028C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
U01-DK-105556 / / GF / International
N01HC95165 / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
HHSN268201300047C / HL / NHLBI NIH HHS / United States
HHSN268201300050C / HL / NHLBI NIH HHS / United States
UL1-TR-001079 / / MESA / International
N01HC65226 / HL / NHLBI NIH HHS / United States
M01 RR007122 / RR / NCRR NIH HHS / United States
N01-HC-95169 / / MESA / International
N01 HC095162 / HC / NHLBI NIH HHS / United States
N01-HC-95161 / / MESA / International
N01-HC-95159 / / MESA / International
N01HC95167 / HL / NHLBI NIH HHS / United States
N01 HC065226 / HC / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01-HC-95164 / / MESA / International
HHSN268201300047C / / JHS / International
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01-DK-070941 / / GF / International
R01 DK053591 / DK / NIDDK NIH HHS / United States
U01-HG004729 / / GENEVA / International
HHSN268201100007I / HL / NHLBI NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
HHSN268201300046C / HL / NHLBI NIH HHS / United States
HHSN268201300026C / / University of Alabama at Birmingham / International
N01-HC-95167 / / MESA / International
HHSN268201300029C / / Kaiser Foundation Research Institute / International
P20 GM121334 / GM / NIGMS NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
HHSN268201300029C / HL / NHLBI NIH HHS / United States
R01-DK-066358 / / GF / International
K99-DK-081350 / / GF / International
R01 HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201300025C / / University of Alabama at Birmingham / International
N01 HC095161 / HC / NHLBI NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
N01 HC095168 / HC / NHLBI NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
HHSN268201300027C / / Northwestern University / International
HHSN268201300046C / / JHS / International
R01-DK-053591 / / GF / International
R01HL086694 / HL / NHLBI NIH HHS / United States
HHSN268201300028C / / University of Minnesota / International