Date of Graduation

5-2015

Document Type

Dissertation (PhD)

Program Affiliation

Human and Molecular Genetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Craig L. Hanis, Ph.D.

Committee Member

Carol J. Etzel, Ph.D.

Committee Member

Xiaoming Liu, Ph.D.

Committee Member

Paul A. Scheet, Ph.D.

Committee Member

Elaine Symanski, Ph.D.

Abstract

Currently, over two-thirds of Americans are classified as over-weight or obese. Obesity increases risk for many other diseases including type 2 diabetes, heart disease, stroke, and cancer, making obesity the largest public health problem in America and most other Westernized nations. Hispanics have a higher rate of both obesity and type 2 diabetes, making them a particularly interesting population in which to study obesity. For the last 33 years, the Starr County Health Studies has collected an array of phenotypes and biological samples from residents of Starr County, along Texas-Mexico border. This study includes 825 subjects who were not known to have diabetes at ascertainment. These subjects have now been seen a second time, on average 8.5 years later. At both visits we measured several aspects of obesity including BMI, bioimpedance to estimate percent body fat, and waist, hip, and arm circumferences. By using multivariate approaches to leverage the array of obesity measures, we have better captured both the amount of adipose tissue and the location of fat deposits.

To assess association of obesity related traits with genetic variation from both genome-wide array data imputed to 1000 Genomes Phase 1 integrated dataset and exome sequencing, both gene-based and single variant tests were conducted. Through these single variant tests, we identified an association with waist to hip ratio and low frequency variants, in two adjacent GABA receptor subunit genes, GABRB2 and GABRA6, including a nonsynonymous variant in GABRA6. Additional associations include an association with a composite measure of adiposity that encompasses degree of adiposity and location of excess fat above or below the waist and TREK1, a gene responsible for trafficking the GABAA receptor to the cell membrane. Gene based tests of rare variants yielded associations between central versus peripheral adiposity and ACSL1, a gene involved in triglyceride biosynthesis. Further replication is required to confirm these associations. While the importance of neuronal signaling pathways in body fat distribution has long been known, many aspects of these pathways are poorly understood. Better understanding of these pathways may identify potential pharmaceutical targets.

Keywords

adiposity, GABA receptor, whole exome sequencing