Obesity has become an epidemic in the United States and worldwide. During the past few years, genome-wide association studies (GWAS) have identified ~50 loci for obesity. However, those loci only account for small proportion (<5%) of the heritability of obesity, and the current GWAS have given us little insight into how these genetic variants are linked with obesity, and how they may response to environment (diet and lifestyle) modulation. The goal of this study is to address these GWAS limitations to provide further insights into a system-based understanding of the genetics of obesity. We propose to apply newly-developed pathway-based analysis by combining functional pathways, genetics of gene expression (GGE) analysis, and genome scans to identify novel obesity loci beyond conventional GWAS, in 11,577 men and women from the Nurses'Health Study (NHS) and Health Professionals'Follow-up Study (HPFS) with genome scans. The in silico validation will be performed in Framingham Heart Study (N=9,171) and GIANT consortium (N=121,600). We will determine the newly-identified and the established obesity variants in 811 individuals from a 2-year randomized diet intervention study, the POUNDS LOST trial. We will examine genetic effects on the 2-year weight changes in response to weight-loss diets varying in macronutrient compositions. The validation will be conducted in a separately-funded 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT, n=322). We will also assess the genetic effects on the markers regulating energy intake and energy expenditure, including: 1) psychiatric measures for food craving, fullness, and hunger;2) energy expenditure (resting metabolic rate [RMR] and total energy expenditure [TEE]);3) biochemical markers of brain-gut- adipose axis, including leptin, insulin, glucose, ghrelin, GLP-1, adiponectin and RBP4;and 4) adipose gene expression profile. Because the genome-wide scans, diet intervention, and measures of energy intakes and expenditure, adipose gene expression, as well as body composition are funded through other grants, the proposed project will be extremely cost-effective. We have assembled a solid group of experienced collaborators with expertise in genetic epidemiology, statistics, pathway GGE analyses, clinical trial, obesity and nutrition. We believe that the unprecedented resources available in this project will provide a unique opportunity to identify novel genetic factors for obesity, and to get insights into the mechanisms of genetic and dietary factors in controlling long-term weight change in humans.

Public Health Relevance

The proposed study integrating novel pathway GGE analyses in large cohorts and comprehensive analyses on the genetic effects on long-term weight loss and mechanisms in response to weight-loss diets in randomized intervention trials would provide extraordinarily important and novel evidence to unravel theetiology of obesity, and have significant public health and clinical implications. Establishing relationship between genetic variants and diets in determining weight change will help identify individuals at high risk for obesity especially when adherent to specific diet. In addition, identifying genes related to energy intakes and expenditure relating to weight change should enable the discovery of new prevention and pharmaceutical treatment for obesity, and could significantly enhance the effectiveness of clinical patient care and assist personalized dietary approaches in prevention of obesity and related metabolic disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Karp, Robert W
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Harvard University
Schools of Public Health
United States
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Huang, Tao; Zheng, Yan; Hruby, Adela et al. (2017) Dietary Protein Modifies the Effect of the MC4R Genotype on 2-Year Changes in Appetite and Food Craving: The POUNDS Lost Trial. J Nutr 147:439-444
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
Lv, Jun; Yu, Canqing; Guo, Yu et al. (2017) Gallstone Disease and the Risk of Type 2 Diabetes. Sci Rep 7:15853
Qi, Lu; Ma, Wenjie; Heianza, Yoriko et al. (2017) Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease. Arterioscler Thromb Vasc Biol 37:2204-2212
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
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
Sun, Dianjianyi; Wang, Tiange; Heianza, Yoriko et al. (2017) A History of Asthma From Childhood and Left Ventricular Mass in Asymptomatic Young Adults: The Bogalusa Heart Study. JACC Heart Fail 5:497-504
He, Hao; Sun, Dianjianyi; Zeng, Yong et al. (2017) A Systems Genetics Approach Identified GPD1L and its Molecular Mechanism for Obesity in Human Adipose Tissue. Sci Rep 7:1799
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

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