肥胖症是一种具有高度遗传性的疾病，但迄今所报告的遗传关联性只能解释身体质量指数遗传变化的很小一部分。两个小组报告了染色体16p11.2上所发生的基因删除，它们也许可解释所谓“高外显率”突变中部分“缺失的遗传性”。这类突变很罕见，但一旦存在，就会以非常高的频率被与严重肥胖症联系起来。这跟与临床症候联系不是很密切的更为常见的基因缺陷形成对比。
Bochukova等人在300个患有严重早发性肥胖周的患者身上发现了罕见的复发性版本数突变体，它们是由涉及包括SH2B1（已知参与“莱普亭”和胰岛素的信号作用）在内的几种基因的删除造成的。这些患者很多还患有神经发育症。Walters等人在31个患有一种以前未被识别出的极端肥胖症的患者的染色体16p11.2上识别出至少593个千碱基对的删除。他们用来识别病灶的策略（利用数量较少的、表现型较好的极端表现型人群进行研究，继之以定向全基因组关联研究和“population cohort”研究）有望作为一种手段，来识别更具普遍性的复杂代谢疾病中“缺失的遗传性”。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 463, 666-670 (4 February 2010) | doi:10.1038/nature08689
Large, rare chromosomal deletions associated with severe early-onset obesity
Elena G. Bochukova1,5, Ni Huang2,5, Julia Keogh1, Elana Henning1, Carolin Purmann1, Kasia Blaszczyk1, Sadia Saeed1, Julian Hamilton-Shield3, Jill Clayton-Smith4, Stephen O’Rahilly1, Matthew E. Hurles2 & I. Sadaf Farooqi1
1 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
2 Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
3 Bristol Children’s Hospital, Bristol BS2 8BG, UK
4 Genetic Medicine, St Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK
5 These authors contributed equally to this work.
Obesity is a highly heritable and genetically heterogeneous disorder1. 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 autism2, 3, 4 and mental retardation5; 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 signalling6. 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.
