既往的研究未能解释肥胖症大部分的遗传度。为了寻找肥胖的致病基因，我们对227例肥胖患者及221例正常体重受试者进行了外显子组测序。我们发现一例肥胖先证者携带DGAT2无义突变c.382C>T(p.Arg128*)，体外实验证明DGAT2的无义突变抑制了甘油三酯的合成。作为甘油三脂合成的关键酶，DGAT2的功能异常可能是肥胖发生的重要原因。我们对先证者的核心家系进行了外显子组测序，结果发现FAAH c.G944T(p.R315I)。上述结果提示FAAH的错义突变可能逆转了DGAT2无义突变的表型从而导致肥胖。我们将借助DGAT2 c.382C>T、FAAH c.G944T点突变的转基因小鼠和HepG2细胞模型，从体内外水平证明DGAT2和FAAH参与甘油三酯合成与体重调节。本研究是应用外显子组测序的方法揭示肥胖症遗传缺陷的成功范例。上述问题的阐明将为肥胖发生机制和干预研究提供新的方向。

Previous efforts have failed to account for most of the apparent genetic risk variance of obesity. To find the obesity causative genes, we exome sequenced 227 obese patients and 221 controls. We have found one obese proband had a nonsense mutation c.382C>T(p.Arg128*) in DGAT2 and the biosynthesis of triglycerides is inhibited with the nonsense mutation of DGAT2 in vitro. As the key enzyme involved in biosynthesis of triglycerides, dysfunction of DGAT2 may be an important regulator of obesity. In addition, we exome sequenced the trios, and identified a FAAH missense mutation c.G944T(p.R315I). These results suggest that the FAAH mutation may reverse the phenotype of nonsense mutation of DGAT2 and lead to obesity. In this study, we will use DGAT2 c.382C>T and FAAHc.G944T transgenic mouse model as well as HepG2 cell lines to demonstrate the important role of DGAT2 and FAAH in triglycerides biosynthesis and body weight control. This study further illustrates the successful application of exome sequencing to uncover genetic defects in obesity. Altogether, our study will provide a new direction for the pathogenesis and therapy of obesity.