Diels Sara, Huybreghts Sander, Van Hoorenbeeck Kim, Massa Guy, Verrijken An, Verhulst Stijn L, Van Gaal Luc F, Van Hul Wim
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Department of Pediatrics, Antwerp University Hospital, Antwerp, Belgium.
Mol Genet Metab Rep. 2020 Oct 28;25:100656. doi: 10.1016/j.ymgmr.2020.100656. eCollection 2020 Dec.
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 , , and . A significant increase in copy number loss(es) was perceived in our patient cohort (MAF = 27%; = 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 , , and 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.
全基因组拷贝数研究将11号染色体q11区域与肥胖症联系起来。由于该区域富含嗅觉受体基因，我们推测嗅觉受体基因的遗传变异可能与肥胖症的发病机制有关。应用多重扩增定量分析技术，对627例肥胖患者和330例体重正常个体的11号染色体q11区域进行拷贝数变异筛查。发现了一个±80 kb的缺失，内部保留了一段1.3 kb的片段，覆盖了三个嗅觉受体基因 、 和 。在我们的患者队列中，拷贝数缺失显著增加（MAF = 27%； = 0.02）。对代谢相关组织进行基因表达谱分析，以评估肥胖易感位点的功能影响。三个11q11基因均存在于内脏和皮下脂肪组织中，而在肝脏中未检测到表达。这些结果支持了“代谢系统”假说，并表明 、 和 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，我们的研究证明了富含嗅觉受体区域的结构变异在复杂疾病中的作用，并将11q11缺失定义为肥胖的一个风险因素。
