Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability.

肥胖在遗传上具有异质性，有单基因和复杂多基因形式。通过对 2,737 例严重肥胖病例和 6,704 例对照进行外显子组和靶向测序，我们发现了三个基因（ PHIP 、 DGKI和ZMYM4 ）在病例中具有超额的非常罕见的预测有害变异。在细胞中，我们发现核 PHIP（pleckstrin 同源域相互作用蛋白）直接增强阿片黑皮素原 (POMC) 的转录，POMC 是一种抑制食欲的神经肽。肥胖相关的PHIP变异抑制 POMC 转录。我们证明 PHIP 通过中央黑皮质素信号传导的转录调节参与人体能量稳态，对于肥胖和发育迟缓患者具有潜在的诊断和治疗意义。此外，我们发现预测的有害变异负担过重，涉及与肥胖全基因组关联研究中最接近位点的基因。影响肥胖的基因和基因组具有不同的外显率，为肥胖遗传结构中因果关系的连续性提供了令人信服的证据，并解释了其一些缺失的遗传性。