Presentation Abstract

Session: 10-A-Genetic Epidemiology
Friday, Mar 25, 2011, 10:30 AM -12:00 PM
Presentation: 040 - Genome-Wide Association Study of Body Mass Index in 33,525 African Americans Validates Four Loci Previously Identified in Europeans and Reveals Two Novel Loci
Location: Atrium Ballroom A
Pres. Time: Friday, Mar 25, 2011, 11:00 AM -11:15 AM
Category: +EPI - Genetic Epidemiology
Keywords: Genetics; Obesity
Author(s): Keri L Monda, Kira T Taylor, Leslie A Lange, Univ of North Carolina at Chapel Hill, Chapel Hill, NC; Gary K Chen, Univ of Southern California, Los Angeles, CA; George J Papanicolaou, NHLBI, Bethesda, MD; Joel N Hirschhorn, Harvard Medical Sch, Boston, MA; Kari E North, Univ of North Carolina at Chapel Hill, Chapel Hill, NC; Christopher A Haiman, Univ of Southern California, Los Angeles, CA; The CARe Consortium Adiposity Working Group; The Genome-wide Association Studies of Breast andProstate Cancer in African Americans Consortium; The African American BMI Consortium
Abstract: Obesity is a well-established risk factor for several chronic diseases and presents a substantial public health challenge. While environment plays a prominent role, substantial evidence exists for a genetic contribution to body mass. Over 30 loci influencing body mass index (BMI) have been discovered through genome-wide association studies (GWAS) in individuals of European descent, but far fewer have been conducted in individuals of other ancestries. Our study addresses important and key questions motivated by recent progress in genetic mapping of complex traits: are loci identified in populations of European ancestry of consequence in African Americans (AA), and can additional novel associations be detected? We present results from the largest GWAS to date of BMI in individuals of African descent: 33525 adults (11253 men, 22272 women) from 29 cohorts. Cohorts used an additive model to test for association between ~2.5 million genotyped and imputed SNPs and BMI; summary results were meta-analyzed using the inverse variance method. All analyses were adjusted for admixture and imputation was performed using a combination of the HapMap YRI and CEU panels. Five loci achieved genome-wide significance (p<5.0E-8), in or near BDNF, RP11/GNPDA2, FTO, MC4R, and PCSK1/CAST. Three significant loci were identified in women only, 2 included in the sex-combined analysis (BDNF, RP11/GNPDA2), and 1 additional locus near KLHL32. Novel loci include PCSK1, a candidate gene involved in monogenic forms of obesity, providing further evidence of genes involved in both Mendelian and common obesity, and KLHL32, which has not been previously associated with BMI. Associations within loci containing RP11/GNPDA2, BDNF, FTO, and MC4R validate previous findings from GWAS in Caucasians. We identified the same SNP for RP11/GNPDA2, and a different SNP with moderate linkage disequilibrium (LD) to a previously-mapped SNP for BDNF (r2=0.72 AA, r2=0.90 CEU). For FTO and MC4R, identified SNPs show different LD patterns to the lead Caucasian SNPs, potentially allowing for further signal localization. Earlier studies in African Americans reported our FTO SNP in fine-mapping analyses and there has been suggestive evidence of association with our MC4R SNP. These results demonstrate both the ability to map novel loci in African Americans as well as the relevance of genetic risk variants for a number of previously identified obesity susceptibility loci. Findings also emphasize the utility in localizing causal DNA variants by leveraging differences in nucleotide diversity and LD patterns among divergent populations to refine association boundaries and prioritize SNPs for functional evaluation.
Disclosures:  K.L. Monda: None. K.T. Taylor: None. L.A. Lange: None. G.K. Chen: None. G.J. Papanicolaou: None. J.N. Hirschhorn: None. K.E. North: None. C.A. Haiman: None.