The goal of this R01DK78616 renewal is to identify new type 2 diabetes (T2D) quantitative trait (QT) loci in a large trans-four-ethnic sample (N~103,000: ~26K African American, ~46K European, ~14K Hispanic and ~17K Asian) using staged genome-wide association studies with meta-analysis (GWAS-MA). In the trans- ethnic sample we will further test gene-environment and gene-gene interactions and gene pathways, and in longitudinal data, test candidate loci for physiological effects and for T2D prediction. Our links with other NIDDK studies offer immediate follow-up for next-generation sequencing (U01 DK085526) and trials of clinical application of genetics for T2D prevention (R21 DK084527). The significant recent, dramatic increase in T2D in the U.S., especially in minority groups, is an escalating clinical and public health challenge. Variation in genetic background coupled with increasing obesity accounts for rising T2D in the U.S.. In people of European ancestry, large-scale GWAS-MA have successfully outlined T2D common genetic architecture, with consortia studies led by our group and our collaborators recently contributing >50 new T2D risk or T2D QT loci. Large trans-ethnic GWAS-MA is a key next step in T2D gene discovery.
Specific Aims are to: 1) Identify novel T2D QT-associated variants using GWAS-MA in large, non-diabetic, trans-ethnic samples. We hypothesize that: a) staged GWAS-MA of T2D QTs in a large non-diabetic African American sample will identify novel loci associated with T2D physiology and T2D risk and b) joining the African American T2D QT GWAS-MA with three other groups for a large trans-four-ethnic T2D QT GWAS-MA will identify additional loci;2) Use the large trans-ethnic sample to find more loci, fine map, and suggest mechanism by tests of gene-environment, gene-gene and gene pathway analyses, specifically, accounting for SNP x BMI, weight change, ethnicity and other interactors;and 3) Use longitudinal population-based data to iluminate the evolution of T2D physiology over time, define the allelic spectrum of risk in U.S. ethnic groups, and test if novel T2D-related variants aid T2D risk prediction. The trans-four-ethnic GWAS-MA will provide an unparalleled resource for genetic discovery, studies of interactions and pathways hypothesized to underlie T2D and its related QTs, and help better define the value of T2D genetics for physiological targeting, population prediction and personalized prevention to improve health in minority and non-minority groups the U.S..

Public Health Relevance

We aim to identify novel type 2 diabetes (T2D) quantitative trait (QT) loci in ~103,000 individuals of African American, European, Hispanic and East Asian ancestry using staged genome-wide association study with meta-analysis. QTs include fasting glucose, insulin and hemoglobin A1c. T2D is increasing dramatically in the U.S., especially in minority groups. Current approaches to control of T2D seem insufficient, and new approaches are needed. Large-scale genetic studies have successfully outlined the common genetic architecture of T2D and T2D QTs in people of European ancestry.
We aim to provide the same knowledge for minority groups in the U.S. especially affected by T2D to improve diagnosis, prevention and care.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M2))
Program Officer
Mckeon, Catherine T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Wang, Tiange; Huang, Tao; Kang, Jae H et al. (2017) Habitual coffee consumption and genetic predisposition to obesity: gene-diet interaction analyses in three US prospective studies. BMC Med 15:97
Merino, Jordi; Leong, Aaron; Posner, Daniel C et al. (2017) Genetically Driven Hyperglycemia Increases Risk of Coronary Artery Disease Separately From Type 2 Diabetes. Diabetes Care 40:687-693
Ma, Wenjie; Huang, Tao; Heianza, Yoriko et al. (2017) Genetic Variations of Circulating Adiponectin Levels Modulate Changes in Appetite in Response to Weight-Loss Diets. J Clin Endocrinol Metab 102:316-325
Joehanes, Roby; Zhang, Xiaoling; Huan, Tianxiao et al. (2017) Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies. Genome Biol 18:16
Manning, Alisa (see original citation for additional authors) (2017) A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. Diabetes 66:2019-2032
Kraja, Aldi T; Cook, James P; Warren, Helen R et al. (2017) New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475?000 Individuals. Circ Cardiovasc Genet 10:
Justice, Anne E (see original citation for additional authors) (2017) Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits. Nat Commun 8:14977
Wang, Tiange; Huang, Tao; Heianza, Yoriko et al. (2017) Genetic Susceptibility, Change in Physical Activity, and Long-term Weight Gain. Diabetes 66:2704-2712
Scott, Robert A; Scott, Laura J; M├Ągi, Reedik et al. (2017) An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes 66:2888-2902
Heianza, Yoriko; Sun, Dianjianyi; Wang, Tiange et al. (2017) Starch Digestion-Related Amylase Genetic Variant Affects 2-Year Changes in Adiposity in Response to Weight-Loss Diets: The POUNDS Lost Trial. Diabetes 66:2416-2423

Showing the most recent 10 out of 102 publications