This is an application for a competitive renewal of R01DK44073 to complete Phase III of a genetic study aimed at mapping and eventually identifying genes for human obesity. During Phases I-II, we accrued over 300 families segregating extreme obesity and normal weight. We completed 60 papers, including two genome scans. We detected linkage to several genomic regions and examined candidate genes and sequences within selected regions. We also completed mutation screening of candidate genes, genetic association studies, and linkage disequilibrium analyses. During Phase III we propose to conduct fine linkage and linkage disequilibrium mapping in a region of chromosome 12 that provided the strongest and most consistent support for linkage across obesity phenotypes and analytic methods in our most recent genome scan. The results meet the most conservative criteria for genome wide significance.
Specific Aim 1 : We will conduct fine linkage mapping studies for the peak linkage signal found in our second-generation genome scan on chromosome 12. We will use 305 families segregating extreme obesity and normal weight. We will conduct combined linkage and linkage disequilibrium studies of the same data. Our goal is to reduce the confidence interval by about 25-30% to approximately 8 Mb.
Specific Aim 2. Beginning in year 2 of the project, we will conduct linkage disequilibrium mapping studies using 500 proband-parent triads (collected in a separate project, R01DK56210, but with similar ascertainment criteria) for an 8 Mb interval of chromosome 12.
Specific Aim 3. We will identify up to 5 candidate genes or expressed sequences in close physical proximity to identified marker and screen polymorphisms for associations with obesity phenotypes. Obesity is an increasingly prevalent condition having serious consequences for health and quality of life. The identification of genes for common forms of obesity should lead to more individualized therapies and more effective prevention strategies. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044073-15
Application #
7338318
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Karp, Robert W
Project Start
1991-07-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2010-01-31
Support Year
15
Fiscal Year
2008
Total Cost
$532,008
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Li, Wei-Dong; Jiao, Hongxiao; Wang, Kai et al. (2015) Pathway-Based Genome-wide Association Studies Reveal That the Rac1 Pathway Is Associated with Plasma Adiponectin Levels. Sci Rep 5:13422
Jiao, Hongxiao; Wang, Kai; Yang, Fuhua et al. (2015) Pathway-Based Genome-Wide Association Studies for Plasma Triglycerides in Obese Females and Normal-Weight Controls. PLoS One 10:e0134923
Li, Wei-Dong; Jiao, Hongxiao; Wang, Kai et al. (2013) A genome wide association study of plasma uric acid levels in obese cases and never-overweight controls. Obesity (Silver Spring) 21:E490-4
Wang, Kai; Li, Wei-Dong; Zhang, Clarence K et al. (2011) A genome-wide association study on obesity and obesity-related traits. PLoS One 6:e18939
Wang, Kai; Li, Wei-Dong; Glessner, Joseph T et al. (2010) Large copy-number variations are enriched in cases with moderate to extreme obesity. Diabetes 59:2690-4
Price, R Arlen; Li, Wei-Dong; Zhao, Hongyu (2008) FTO gene SNPs associated with extreme obesity in cases, controls and extremely discordant sister pairs. BMC Med Genet 9:4
Saunders, Catherine L; Chiodini, Benedetta D; Sham, Pak et al. (2007) Meta-analysis of genome-wide linkage studies in BMI and obesity. Obesity (Silver Spring) 15:2263-75
Dong, C; Li, W-D; Li, D et al. (2006) Extreme obesity is associated with attempted suicides: results from a family study. Int J Obes (Lond) 30:388-90
Malhotra, Alka; Coon, Hilary; Feitosa, Mary F et al. (2005) Meta-analysis of genome-wide linkage studies for quantitative lipid traits in African Americans. Hum Mol Genet 14:3955-62
Li, Wei-Dong; Dong, Chuanhui; Li, Ding et al. (2005) A genome scan for serum triglyceride in obese nuclear families. J Lipid Res 46:432-8

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