Large, rare chromosomal deletions associated with severe early-onset obesity.
Large, rare chromosomal deletions associated with severe early-onset obesity.
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肥胖症是一种高度遗传的遗传性异质性疾病，我们研究了300名严重的早期发作肥胖症患者的拷贝数变化对肥胖症的贡献，其中143例也有较大的延迟（> 500千倍）。 1％）与7,366个对照相比，缺失显着富含患者（p <0.001）。患者但在对照中缺乏或较低的患病率。严重的肥胖症患者具有较大的NOVO 16P11.2缺失，通过以前与自闭症和精神降低的593 kilobase区域延伸患者在1,062例严重肥胖症患者的独立样本中还具有轻度的发育迟缓，在另外两个患者中发现了较小的16p11.2缺失。已知参与瘦素和胰岛素信号传导该拷贝数的变化对人肥胖的遗传结构产生了重大贡献。
Obesity is a highly heritable and genetically heterogeneous disorder. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P < 5 × 10−5). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.
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