Genome-wide copy number surveys associated chromosome 11q11 with obesity. As this is an olfactory receptor-rich region, we hypothesize that genetic variation in olfactory receptor genes might be implicated in the pathogenesis of obesity. Multiplex Amplicon Quantification analysis was applied to screen for copy number variants at chromosome 11q11 in 627 patients with obesity and 330 healthy-weight individuals. A ± 80 kb deletion with an internally 1.3 kb retained segment was identified, covering the three olfactory receptor genes OR4C11, OR4P4, and OR4S2. A significant increase in copy number loss(es) was perceived in our patient cohort (MAF = 27%; p = 0.02). Gene expression profiling in metabolic relevant tissues was performed to evaluate the functional impact of the obesity susceptible locus. All three 11q11 genes were present in visceral and subcutaneous adipose tissue while no expression was perceived in the liver. These results support the ‘metabolic system’ hypothesis and imply that gene disruption of OR4C11, OR4P4, and OR4S2 will negatively influence energy metabolism, ultimately leading to fat accumulation and obesity. Our study thus demonstrates a role for structural variation within olfactory receptor-rich regions in complex diseases and defines the 11q11 deletion as a risk factor for obesity.

全基因组拷贝数调查与肥胖症相关的染色体11q11。由于这是一个富含嗅觉受体的区域，因此我们假设嗅觉受体基因的遗传变异可能与肥胖的发病机理有关。应用多重扩增子定量分析筛选了627名肥胖患者和330名健康体重个体的11q11号染色体拷贝数变异。鉴定出具有内部1.3 kb保留片段的±80 kb缺失，涵盖了三个嗅觉受体基因OR4C11，OR4P4和OR4S2。在我们的患者队列中，感知到的拷贝数损失显着增加（MAF = 27％；p = 0.02）。在代谢相关组织中进行基因表达谱分析以评估肥胖易感基因座的功能影响。所有三个11q11基因均存在于内脏和皮下脂肪组织中，而在肝脏中未发现任何表达。这些结果支持“代谢系统”假说，并暗示OR4C11，OR4P4和OR4S2的基因破坏将对能量代谢产生负面影响，最终导致脂肪堆积和肥胖。因此，我们的研究证明了复杂疾病中富含嗅觉受体的区域内结构变异的作用，并将11q11缺失定义为肥胖的危险因素。