MRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Metabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Nat Genet. 2024 Apr;56(4):579-584. doi: 10.1038/s41588-024-01694-x. Epub 2024 Apr 4.
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，并且具有很大的遗传成分。为了确定新的遗传决定因素，我们对多达 587,027 个人的成年人体重指数 (BMI) 进行了外显子组测序分析。我们在两个基因（BSN 和 APBA1）中发现了罕见的功能丧失性变体，其影响明显大于 MC4R 等已确立的肥胖基因。与大多数其他肥胖相关基因不同，BSN 和 APBA1 中的罕见变体与儿童肥胖的正常变化无关。此外，BSN 蛋白截断变体 (PTV) 放大了与 BMI 相关的常见遗传变体的影响，常见变异多基因评分在 BSN PTV 携带者中的作用是无携带者的两倍。最后，我们探索了 BSN PTV 携带者的血浆蛋白质组特征以及人类诱导多能干细胞衍生的下丘脑神经元中 BSN 缺失的功能后果。总的来说，我们的研究结果表明，突触功能的退行性过程与成年期肥胖的病因有关。
