Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015, Lausanne, Switzerland.
Quartz Bio, Avenue de Sécheron 15, 1202, Geneva, Switzerland.
Nat Commun. 2017 Dec 12;8(1):2084. doi: 10.1038/s41467-017-02182-z.
Thousands of genetic variants have been associated with complex traits through genome-wide association studies. However, the functional variants or mechanistic consequences remain elusive. Intermediate traits such as gene expression or protein levels are good proxies of the metabolic state of an organism. Proteome analysis especially can provide new insights into the molecular mechanisms of complex traits like obesity. The role of genetic variation in determining protein level variation has not been assessed in obesity. To address this, we design a large-scale protein quantitative trait locus (pQTL) analysis based on a set of 1129 proteins from 494 obese subjects before and after a weight loss intervention. This reveals 55 BMI-associated cis-pQTLs and trans-pQTLs at baseline and 3 trans-pQTLs after the intervention. We provide evidence for distinct genetic mechanisms regulating BMI-associated proteins before and after weight loss. Finally, by functional analysis, we identify and validate FAM46A as a trans regulator for leptin.
通过全基因组关联研究，已经发现数千个与复杂性状相关的遗传变异。然而，功能变异或机制后果仍然难以捉摸。中间性状，如基因表达或蛋白质水平，是生物体代谢状态的良好代表。蛋白质组分析特别可以为肥胖等复杂性状的分子机制提供新的见解。遗传变异在决定蛋白质水平变异中的作用在肥胖中尚未得到评估。为了解决这个问题，我们设计了一项大规模的蛋白质数量性状基因座（pQTL）分析，该分析基于一组 1129 种蛋白质，来自 494 名肥胖受试者在减肥干预前后的样本。这揭示了 55 个与 BMI 相关的顺式-pQTLs 和 3 个在干预后的反式-pQTLs。我们提供了证据表明，在减肥前后，调节 BMI 相关蛋白的遗传机制是不同的。最后，通过功能分析，我们确定并验证了 FAM46A 是瘦素的一个反式调节剂。
