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To identify variants that potentially impact human body fat via a role in adipogenesis, we analyzed whole-exome sequence data from a population-based sample of 6809 American Indians with longitudinal measures of BMI. A total of 623,236 exonic variants were detected and those that met the following criteria were prioritized for functional analysis: 1) non-synonymous, stop-gain or frameshift that occurred in ≥5 individuals; 2) a Combined Annotation Dependent Depletion (CADD) score ≥10 (top 10% of deleterious variants); 3) evidence for association with maximum BMI in adulthood (n=6002) or maximum BMI z-score in childhood (n=4882) (P In conclusion, whole-exome sequencing followed by in vitro analysis of lipid accumulation in OP9 cells has identified coding variants that may impact BMI via a role in adipogenesis. Disclosure Y.L. Muller: None. S.E. Day: None. C. Koroglu: None. S. Kobes: None. R.L. Hanson: None. W.C. Knowler: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. C. Van Hout: Employee; Self; Regeneron Genetics Center. N. Gosalia: None. A.R. Shuldiner: Employee; Self; Regeneron Genetics Center. Stock/Shareholder; Self; Regeneron Pharmaceuticals. C. Bogardus: None. L. Baier: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

Identification of high-impact loss-of-function variants for common disease is challenging because these variants are typically rare and thus statistical power is low when sample sizes are limited. In this study, we utilized whole-exome variant detection, variant prediction programs, tissue expression data, and case-control analysis to identify potentially highly penetrant obesity-susceptibility variants for prioritization for functional testing. Whole-exome sequencing was performed on DNA samples collected from a longitudinal, population-based study of American Indians (N=5432; maximum BMI recorded at ≥18 years). Among the 1 million biallelic SNVs detected in this cohort, those that were exonic or splicing, have minor allele frequency (MAF) ≤0.05, predicted to be damaging (CADD score ≥15), and located in genes expressed in hypothalamus were selected for analysis. These selection criteria resulted in 94,444 SNVs, and odds ratios were calculated for them by comparing the group of individuals with BMI in the top 5th percentile for this population (N=271, BMI ≥53.13 kg/m2) vs. those below the median (N=2,717, BMI Disclosure C. Koroglu Altok: None. P. Piaggi: None. M. Traurig: None. R.L. Hanson: None. W.C. Knowler: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. N. Gosalia: Employee; Self; Regeneron Pharmaceuticals. C.V. Van Hout: Employee; Self; Regeneron Pharmaceuticals. B. Ye: Employee; Self; Regeneron Pharmaceuticals. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. C. Bogardus: None. L.J. Baier: None. Funding National Institutes of Health