Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models¹. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss², and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown^3,4,5,6,7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G³. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource^8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous (‘knockouts’) and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.

生长分化因子 15 （GDF15） 是一种分泌蛋白，在临床前模型中调节食物摄入量、体重和应激反应¹。GDF15 在人体中的生理功能仍不清楚。从药理学上讲，人类的 GDF15 激动作用会引起恶心而不伴有体重减轻²，并且 GDF15 拮抗作用正在临床试验中进行测试，以治疗恶病质和厌食症。人类遗传学指出 GDF15 在妊娠剧吐中的作用，但 GDF15 完全缺失的安全性或影响尚不清楚，尤其是在怀孕期间^3,4,5,6,7。在这里，我们展示了人类 GDF15 功能丧失载体中不存在明显的表型，包括停止增益、移码和完全失活的错义变体 C211G³。这些个体是从巴基斯坦基因组资源^8,9 和基因型召回研究的 75,018 名全外显子组/基因组测序参与者中鉴定出来的，并基于家族招募变异携带先证者。我们描述了 8 个纯合子（“敲除”）和 227 个功能丧失等位基因的杂合子携带者，包括 C211G。GDF15 敲除的年龄从 31 岁到 75 岁不等，有生育能力，有多个孩子，并且没有表现出一致的明显表型，包括代谢功能障碍。我们的数据支持这样一个假设，即 GDF15 不是生育、健康怀孕、胎儿发育或存活到成年所必需的。这些观察结果支持阻断 GDF15 的疗法的安全性。