The objective of the proposed research is to investigate how genetic variation influences weight-related traits during the transition from adolescence to adulthood - a critical risk period for weight gain. Genome wide association studies (GWAS) have identified >70 well-replicated loci influencing weight-related traits, some of which vary by race/ethnicity. Few studies have examined the genetic architecture of these traits during this critical period; the discovered loci are largely common variants that explain only a fraction of the estimated trait heritability. Fine-mapping studies suggest allelic heterogeneity; many causal variants remain to be determined. Recent attention has shifted to coding variants some of which may have larger effect sizes and potential to explain more trait heritability. We build on our successes in R01 HD057194 and capitalize on nationally representative, ethnically diverse, prospective and well-characterized data on 10,581 individuals from the National Longitudinal Study of Adolescent Health (Add Health) to assess the association between weight- related traits and coding variants across a 15-year lifecycle period of dramatic weight gain between adolescence and adulthood. In addition, to make full use of this excellent resource, we combine our data with extant exome data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n>91,000) to further assess associations with adiposity phenotypes, an approach that will be particularly informative and powerful for the discovery of novel coding variants. Further, to fully ensure that we capitalize on the uniqueness of our longitudinal data on adolescent to adult weight gain, we combine our data with two well-characterized, age-matched cohorts with exome data (China Health and Nutrition Survey, CHNS n=1,951; Cebu Longitudinal Health and Nutrition Survey, CLHNS, n=1,691) living under different environmental conditions but experiencing high levels of weight gain analogous to Add Health. Using all three datasets, we will determine the genetic and epidemiological architecture of causal variants; identify functional SNPs and genes; and using advanced and innovative statistical modeling, examine differential genetic effects by age, time, and under varying environmental circumstances to downstream cardiometabolic risk factors (diabetes-, blood pressure-, and inflammatory-related markers). We will test novel hypotheses on tempo and timing of risk as well as address each piece of the complex system linking genetic markers, weight-related outcomes, and cardiometabolic risk factors, in the context of a variety of environmental and behavioral confounders. In sum, these data provide outstanding resources for examining low frequency coding variants associated with weight- related and cardiometabolic traits - a rapidly emerging area of science. Our longitudinal and complex analyses in this understudied age range will provide critical information about risk in the transition from adolescence into adulthood, a period of rapid weight gain when precursors of adult disease are developing. Our work will shed light on the progression of risk to inform efforts to mitigate early development of disease risk.

Public Health Relevance

The objective of the proposed research is to investigate how genetic variants influence temporal changes in body mass index and downstream cardiometabolic risk factors at a vulnerable lifecycle period for weight gain, with differential rik across race/ethnic groups. The proposed research will contribute to the understanding of risk in the transition from adolescence into adulthood, a period of rapid weight gain when precursors of adult disease are developing, in order to inform efforts to mitigate early development of disease risk.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bremer, Andrew
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Public Health
Chapel Hill
United States
Zip Code
Inoue, Yosuke; Qin, Bo; Poti, Jennifer et al. (2018) Epidemiology of Obesity in Adults: Latest Trends. Curr Obes Rep 7:276-288
Fernández-Rhodes, Lindsay; Malinowski, Jennifer R; Wang, Yujie et al. (2018) The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis. PLoS One 13:e0200486
Turcot, Valérie (see original citation for additional authors) (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50:26-41
Marouli, Eirini (see original citation for additional authors) (2017) Rare and low-frequency coding variants alter human adult height. Nature 542:186-190
Fernández-Rhodes, Lindsay; Robinson, Whitney R; Sotres-Alvarez, Daniela et al. (2017) Accuracy of Self-reported Weight in Hispanic/Latino Adults of the Hispanic Community Health Study/Study of Latinos. Epidemiology 28:847-853
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
Graff, M; North, K E; Richardson, A S et al. (2017) BMI loci and longitudinal BMI from adolescence to young adulthood in an ethnically diverse cohort. Int J Obes (Lond) 41:759-768
Graff, Mariaelisa (see original citation for additional authors) (2017) Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults. PLoS Genet 13:e1006972
Fernández-Rhodes, Lindsay; Gong, Jian; Haessler, Jeffrey et al. (2017) Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. Hum Genet 136:771-800
Young, K L; Graff, M; North, K E et al. (2016) Influence of SNP*SNP interaction on BMI in European American adolescents: findings from the National Longitudinal Study of Adolescent Health. Pediatr Obes 11:95-101

Showing the most recent 10 out of 60 publications