The factors that determine an individual’s body weight are highly complex and incompletely understood. Currently, >1,000 genes that are associated with body weight have been identified; however, these variants explain only a small fraction of the population variance in BMI. Over the past few years, whole-exome sequencing has been applied at the population scale, in exome-wide association studies. Now, one such study has identified an association between two genes and severe adult-onset obesity for the first time, with some of the largest effects on obesity risk ever reported.

Next, the researchers assessed the phenotypic profile of people who had protein-truncating variants in BSN or APBA1. Unlike most other genes that are associated with obesity, neither of these genes were associated with childhood body size or puberty timing. They were associated with increased adipose and lean mass in adulthood, but not with adult height or waist-to-hip ratio. People who had the BSN variants also had an increased risk of type 2 diabetes mellitus and of non-alcoholic fatty liver disease. The lack of an association with childhood body size is highly unusual and suggests that there might be novel mechanisms underlying the associations identified in this study.

决定个人体重的因素非常复杂且尚未完全了解。目前，已鉴定出超过 1,000 个与体重相关的基因；然而，这些变异只能解释体重指数总体差异的一小部分。在过去的几年中，全外显子组测序已在人群规模的外显子组关联研究中得到应用。现在，一项此类研究首次确定了两个基因与成人严重肥胖之间的关联，其中一些对肥胖风险的影响是有史以来最大的。

接下来，研究人员评估了BSN或APBA1中具有蛋白质截短变异的人的表型特征。与大多数其他与肥胖相关的基因不同，这些基因都与儿童体型或青春期时间无关。它们与成年期脂肪和瘦体重的增加有关，但与成年身高或腰臀比无关。携带BSN变异的人患2 型糖尿病和非酒精性脂肪肝的风险也会增加。与儿童体型缺乏关联是非常不寻常的，这表明本研究中发现的关联可能存在新的机制。