Defense Date

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Human Genetics

First Advisor

Hermine Maes

Abstract

Obesity is a serious public health crisis and recent estimates of its incidence are the highest in United States history, with 35% and 17% of American adults and children affected, respectively. The clinical definition of adult obesity is operationalized as a body mass index (BMI) greater than 30 kg/m2. Although the prevalence of common obesity has increased dramatically over the past 30 years–largely thought to be due to changes in the environment, such as high calorie diets and sedentary lifestyles—twin and family studies have shown consistently that relative body weight is under considerable genetic influence in both children and adults, with heritability estimates ranging from 40% to 90%. Elucidating the genetic and environmental liability to relative body weight is an important public health endeavor. To further our understanding of the genetics of BMI and common complex obesity, several studies are described that integrate clinical, twin, and genome-wide association (GWAS) methodology in the context of genetic risk scores, clinical risk prediction, development across adolescence into adulthood, and comorbidity with depression symptoms and smoking behavior. First, in two cross-sectional genetic association studies, the utility of genetic risk sum scores (GRSS) were assessed, which summarize the total number of risk alleles, as an alternative form of replication and for potential clinical utility for obesity risk prediction. Next, since there has been only limited research on when during development BMI-associated variants begin influencing BMI, a longitudinal twin study was utilized to assess the effects of adult-validated BMI-SNPs across adolescence into adulthood. In addition, obesity is comorbid with numerous medical conditions including cardiovascular disease, insulin-resistance and some forms of cancer, as well as, various psychiatric disorders including eating disorders, mood disorders, and substance use. The next series of studies aimed to understand phenotypic and genetic associations between BMI/obesity and binge eating disorder (BED), depression symptoms and smoking behavior. Using a clinical sample of overweight and obese women with and without BED, the relationship of BED, food intake and internalizing symptoms of depression and anxiety was examined. Next, twin study methodology was used to investigate if shared genetic and/or environmental liability was responsible for phenotypic associations found between BMI, depression symptoms, and impulsivity. Finally, a genetic association study aimed at investigating whether genetic variants were associated with multiple behaviors, body composition and smoking behavior, or were trait-specific is presented. By utilizing several samples and methodologies and by pursuing methods development, a comprehensive approach is presented that is hoped to represent a more powerful evidence-based strategy to understanding the genetic and environmental determinants of BMI and common complex obesity, along with associated depression symptoms and smoking behavior.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

November 2012

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