We report a CNR1 haplotype (H3, frequency 21.1%) associated with fasting TG and HDL-C levels in 645 study subjects with class III obesity, nested within one of the largest population-based biobanks in the U.S. We localize the genetic effect to a single block of LD containing the CNR1 coding region, and we demonstrate that this effect is only partly dependent upon nutrient intake and physical activity. The gene discussed is CNR1; the disease is obesity due to melanocortin 4 receptor deficiency.