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Quantitative trait loci, G×E and G×G for glycemic traits: response to metformin and placebo in the Diabetes Prevention Program (DPP)

A Correction to this article was published on 12 April 2022

This article has been updated


The complex genetic architecture of type-2-diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify G×E and G×G, we screened markers for patterns indicative of interactions (relationship loci [rQTL] and variance heterogeneity loci [vQTL]). rQTL exist when the correlation between multiple traits varies by genotype and vQTL occur when the variance of a trait differs by genotype (potentially flagging G×G and G×E). In the metformin and placebo arms of the DPP (n = 1762) we screened 280,965 exomic and intergenic SNPs, for rQTL and vQTL patterns in association with year one changes from baseline in glycemia and related traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose and fasting insulin). Significant (p < 1.8 × 10−7) rQTL and vQTL generated a priori hypotheses of individual G×E tests for a SNP × metformin treatment interaction and secondarily for G×G screens. Several rQTL and vQTL identified led to 6 nominally significant (p < 0.05) metformin treatment × SNP interactions (4 for IGI, one insulin, and one glucose) and 12G×G interactions (all IGI) that exceeded experiment-wide significance (p < 4.1 × 10−9). Some loci are directly associated with incident diabetes, and others are rQTL and modify a trait’s relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). rs3197999, an ISI/insulin rQTL, is a possible gene damaging missense mutation in MST1, is associated with ulcerative colitis, sclerosing cholangitis, Crohn’s disease, BMI and coronary artery disease. This study demonstrates evidence for context-dependent effects (G×G & G×E) and the complexity of these T2D-related traits.

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Data availability

In accordance with the NIH Public Access Policy, we continue to provide all manuscripts to PubMed Central including this manuscript DPP/DPPOS has provided the protocols and lifestyle and medication intervention manuals to the public through its public website ( The DPPOS abides by the NIDDK data sharing policy and implementation guidance as required by the NIH/NIDDK (

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The DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. Funding was also provided by the Swedish Research Council and the European Commission (CoG-2015_681742_NASCENT and H2020-MSCAQ: 19 IF-2015-703787). GWAS genotyping in the DPP was supported in part by a grant from the Novo Nordisk Foundation (to PWF). The work of PWF was supported in part by the grant from the European Research Council.

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TJM conceived of the primary idea for the work, performed all the analyses, and wrote most of the manuscript. TJM and KAJ worked on the design, data, results, and writing of the manuscript. All authors PWF, SEK, WCK, KJM, and JCF contributed to interpretation of the results, provided critical intellectual review and content, and approved the final manuscript.

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Correspondence to Taylor J. Maxwell.

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Competing interests

The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication. The funding agency was not represented in the writing group, although all members of the Steering Committee had input into the report’s contents. All authors in the writing group had access to all data. The opinions expressed are those of the investigators and do not necessarily reflect the views of the funding agencies. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. At the time of publication, KJM was an employee of Eli Lilly and Company. Data collection occurred prior to this employment, and data analyses and manuscript preparation were performed independent of Eli Lilly and Company. The other authors declare no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained for all participants and the study was approved by the institutional review boards of each institution.

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Informed consent was obtained from all individual participants included in the study.

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The authors affirm that human research participants provided informed consent for publication of results related to analyses of data obtained for the DPP.

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Maxwell, T.J., Franks, P.W., Kahn, S.E. et al. Quantitative trait loci, G×E and G×G for glycemic traits: response to metformin and placebo in the Diabetes Prevention Program (DPP). J Hum Genet 67, 465–473 (2022).

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