Medical Sequencing at the Extremes of Human Body Mass. N. Ahituv^1,2, N. Kavaslar³, J. Cohen⁴, R. Dent³, R. McPherson³, L.A. Pennacchio^1,2. 1) Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA; 2) US DOE Joint Genome Institute, Walnut Creek, CA; 3) University of Ottawa Heart Institute, Ottawa, Canada; 4) University of Texas South Western, Dallas, TX.
   Human body weight is a quantitative trait with significant and complex heritability. To explore genetic contributors to this phenotype, we undertook a large-scale medical sequencing approach. We resequenced the coding exons and splice junctions of 58 BMI-related genes in 379 obese (average BMI 49.0 kg/m2) and 378 lean (average BMI 19.5 kg/m2) Caucasian individuals. In total, we generated over 90 Mb of sequence and detected 1074 genetic variants, the majority of which were rare (n=822, minor allele frequency <1%) of which 271 result in amino acid substitutions. While familial segregation of several characterized monogenic obesity genes failed to show complete correlation with BMI, analysis of their rare non-synonymous variants showed a significant frequency skew between the obese and lean panels (23 limited to obese versus 10 in lean). We thus used this paradigm as a filter for the other 51 genes and found 6 novel genes that may be implicated with human BMI (DGAT1, DGAT2, NMUR1, PRKAG3, and SIM1 with obesity and NTS with leanness), all showing significantly large skews between the two panels. In addition, using familial segregation analysis on a portion of the rare non-synonymous variants within the remaining novel genes, enabled us to detect other promising BMI-influencing variants. Association analysis of the 252 common variants (>1% minor allele frequency) that we discovered, failed to show any significant correlations with BMI, including previously suggested ones. Combined, these results point out the importance of complete variation identification in human genetic investigations to complement existing strategies focused on common variant mechanisms of disease susceptibility.