Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
Ann N Y Acad Sci. 2010 Dec;1214:180-9. doi: 10.1111/j.1749-6632.2010.05880.x.
Mendelian forms of obesity are already known to account for approximately 5% of the severely obese but are currently underinvestigated. In contrast, there has been much recent concentration on genome-wide single nucleotide polymorphism (SNP) associations in obesity, with particular emphasis given to the role of the fat mass and obesity associated (FTO) gene. Unfortunately, despite the enormous resources devoted to this work, none of the SNP markers in the ∼30 genes discovered to have associations with common obesity have meaningful predictive power. This is very different from the situation for Mendelian obesity, where mutations have very clear effects on phenotype. Study of Mendelian obesity has also added significantly to our understanding of mechanisms of appetite regulation, with all known causative genes being active in the brain and most forming part of the leptin-melanocortin signaling pathway. Investigation of genomic structural variation has also recently revealed deletions causing obesity, sometimes with concomitant neurocognitive dysfunction. Advances in next-generation sequencing are expected to uncover additional highly penetrant causes of obesity. Screening for Mendelian forms of obesity is rarely carried out but holds considerable promise for improved clinical care of these high-risk patients.
孟德尔肥胖形式已经被认为约占严重肥胖者的 5%，但目前研究不足。相比之下，最近人们对肥胖的全基因组单核苷酸多态性（SNP）关联进行了大量研究，特别强调了脂肪量和肥胖相关（FTO）基因的作用。不幸的是，尽管这项工作投入了巨大的资源，但在与常见肥胖相关的约 30 个基因中发现的 SNP 标记都没有有意义的预测能力。这与孟德尔肥胖症的情况非常不同，孟德尔肥胖症的突变对表型有非常明确的影响。对孟德尔肥胖症的研究也极大地增加了我们对食欲调节机制的理解，所有已知的致病基因都在大脑中活跃，其中大多数基因构成了瘦素-黑素皮质素信号通路的一部分。对基因组结构变异的研究最近还揭示了导致肥胖的缺失，有时伴有神经认知功能障碍。下一代测序技术的进步预计将揭示更多肥胖的高外显率病因。对孟德尔肥胖形式的筛查很少进行，但对这些高风险患者的临床治疗有很大的改善潜力。
