Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

肥胖是许多常见疾病的主要危险因素，并且具有显着的遗传成分。为了确定新的遗传决定因素，我们对多达 587,027 名个体的成人体重指数 (BMI) 进行了外显子组序列分析。我们在两个基因（ BSN和APBA1 ）中发现了罕见的功能丧失变异，其影响远远大于公认的肥胖基因（如MC4R ） 。与大多数其他肥胖相关基因相比，BSN和APBA1的罕见变异与儿童肥胖的正常变异无关。此外，BSN蛋白截短变异 (PTV) 放大了与 BMI 相关的常见遗传变异的影响，常见变异多基因评分在BSN PTV 携带者中的影响是非携带者的两倍。最后，我们探讨了BSN PTV 携带者的血浆蛋白质组特征以及BSN缺失对人类诱导多能干细胞来源的下丘脑神经元的功能影响。总的来说，我们的研究结果表明突触功能的退行性过程是成人肥胖的病因。