Genetics and Binge Eating: A Case- Control Pilot Study Tiffany Stewart, Ph.D. Health Behavior Pennington Biomedical Research Center

Specific Aims & Hypotheses Premise: Genes, behaviors, and the environment are intimately related in the etiology and maintenance of obesity. Further, the effects of the genotype can be amplified in an environment that promotes obesity. Primary Aim: To investigate the association between DNA sequence variation in the genes of the leptin-melanocortin pathway and the behavioral phenotype of binge eating. Primary Hypothesis: The DNA sequence variation in the genes of the leptin-melanocortin pathway is associated with a binge eating phenotype, which may contribute to the development of obesity. Secondary Aim: to implement methods to characterize a “pure” binge eating phenotype. Secondary Hypothesis: binge eating behavior is qualitatively different from eating behavior in obese individuals without eating disorders and nonobese individuals without eating disorders. Principal Investigator: Tiffany M. Stewart, Ph.D. Co-Investigators: Claude Bouchard, Ph.D., George Bray, M.D., Tuomo Rankinen, Ph.D., Donna Ryan, M.D., & Don Williamson, Ph.D.

Significance Specific:  Genetic implications: Identification of genetic basis of hyperphagia in humans Reduction of heterogeneity of obesity  Behavioral implications: Implications for diagnosis of binge eating (as well as other eating disorders) Implications for phenotyping of binge eating Overall:  This study is designed to be the first in a series of studies to investigate the relationship between genotypes and eating behaviors in humans.  This research may mark the beginnings of the attainment of knowledge towards the development of treatment programs and/or medications to be utilized in the future treatment of binge eating and/or obesity. Ultimately, this information could aid health care providers in the development of individualized treatment and prevention programs for individuals predisposed to weight gain or behaviors that may lead to inappropriate weight gain.

Participants: Total (N=200)  Cases (BED; N=100)  Controls (non eating disorder; N=100)  Men and Women ages 18-60, Weight range= normal to obese Matched experimental and control groups The present study hypothesizes behavioral phenotypes for genetic association analysis based upon empirical classification data of eating behavior. These behavioral phenotypes will be used to classify individuals. Genetic material, psychological assessment data, and body composition data will be utilized for the analysis of the association between the selected candidate genes and the behavioral phenotype, binge eating. This study will serve as a pilot study to begin recruitment and collect preliminary data for an R21 application submitted to NIH. CNRU Project Summary

Study Progress: Organization & Training IRB approval  The study was approved by the IRB. Study Coordination  Study coordination system in place. Behavioral Phenotyping  Formal training has been completed for members of the psychological assessment team for the complex behavioral phenotyping procedures, particularly with regard to the new binge eating phenotyping, and reliability procedures on these measurements are currently in progress.  Reliability procedures underway. Progression of 99% agreement between interviewers on measurement instruments so far. Genotyping  Structure and procedures in place

Study Achievement: Behavioral Phenotyping System Problematic Descriptions of Binge Eating throughout literature Inconsistencies in Psychological Diagnosis Inconsistencies in Behavioral Phenotyping in Genetic Studies Controversial Outcomes (Branson et al., 2003) Development of a finite Behavioral Phenotyping System Problem: Solution:

Study Achievement: Development of Recruitment System An online recruitment system has been developed and beta tested. This system is thought to overcome many of the obstacles of traditional methods of recruiting and since this study relies on recruiting for its success, it was necessary to develop for this project. The PBRC online recruiting system employs an online and anonymous forum by which individuals can provide PBRC with eating disorder symptom information. The online system notifies potential participants right away if they do not meet criteria for the study. However, if a participant is a possible candidate, based on the inclusion criteria, their information is securely transported to a member of the psychology via electronic mail. A member of the psychology team reviews the participant’s reported symptoms and criteria and contacts the individual directly for their first screening versus an individual with no prior knowledge of BED. This allows for case sensitivity and the likelihood of weeding out non BED cases in the early stages of the study so as to promote a more efficient phenotyping system as well as more efficient study overall. Online recruitment system beta test:  7 days- approximately 55 individuals applied for the study via online screening forms. Traditional recruitment strategies (advertisements and phone calls) will be utilized in conjunction with online strategies. PBRC database as a source of recruitment

Study Progress: Scientific Progress- R21 submission Principal Investigator: Tiffany Stewart, Ph.D. Co-Investigators: Claude Bouchard, Ph.D., George Bray, M.D., Carlos Grilo, Ph.D., Nathan Markward, Ph.D., Tuomo Rankinen, Ph.D., Donna Ryan, M.D., and Donald Williamson, Ph.D. The proposed pilot study is a collaborative effort between the Pennington Biomedical Research Center and Yale University School of Medicine. Application: 1 R21 DK Submitted June 1, 2005 Center for Scientific Review Special Emphasis Panel (NIDDK) Score 235 Overall review: The review viewed the application to have considerable significance for the reduction of the heterogeneity in obesity research, particularly in genetics. The investigative team was judged to have the experience and expertise to successfully conduct the study. The research environment was viewed as a supportive environment for the study. Overall, the review posited that the strengths of the study outweighed the weaknesses. Received CNRU funding to begin recruiting participants and collecting data Resubmitted July 1, 2006 Study will include 600 participants (300 cases, 300 controls)

Key items addressed:  Recruitment Since the submission of the initial proposal, PBRC has added an online recruiting system, which has aided the recruitment process tremendously for this study. We have complete confidence in our recruitment abilities at PBRC for this application.  Genotyping Since the submission of the initial proposal, PBRC has added a new genotype technology system, the Illumina. With the Illumina system, we can increase genotyping volume 10-fold without changing the budget. Consequently, we can include additional candidate genes from the same pathway.  Addition of a statistical geneticist to team. To provide the expertise of statistical genetics of our research team for the present project, we have added Nathan Markward, Ph.D., M.P.H. to the research team to meet this need. Study Progress: Scientific Progress- R21 submission

Significance: CNRU CNRU Funding: “Headstart”- Key to Success of project and program establishment  Addressed R21 revisions: recruiting system development, addition of personnel and coordination team, staff training  Participant incentives  Behavioral phenotyping system development Utilization of behavioral core Collaboration with molecular genetics core

Summary & Future Directions R21 submission June 1, 2005 CNRU funding and study procedures establishment R21 resubmission July 1, 2006 Future Directions: R01 Further establishment of Behavioral Genetics Research Program

Questions/Discussion