论文标题
全基因组的关联和转录组分析揭示了血清生长素蛋白与GFRAL相关
Genome-wide association and transcriptome analysis reveals serum ghrelin to be linked with GFRAL
论文作者
论文摘要
目的：生长素是一种参与能量稳态，食物摄入和葡萄糖代谢的调节的甲基肽激素。血清水平会增加预期一顿饭，然后下降。生长素分泌的潜在遗传机制尚不清楚。方法：在1501名受试者中从基于人群的生命成分样本中选择过夜后，测量了总血清生长素素。进行了全基因组关联研究（GWAS）。基于基因的表达关联分析（全转录组联想研究（TWA））是使用Metaxcan进行的。结果：在GWAS中，三个基因座达到了全基因组的意义：含有氧化还原酶基因的WW域（WWOX; P = 1.80E-10）在16q23.3-24.1染色体上（SNP：RS76823993）；在7q35-Q36（SNP：RS192092592）上与接触蛋白相关的蛋白质样2基因（CNTNAP2; P = 9.0E-9），以及在Chromosome 3p25.3（SNP = 2.72E-8）3P25.3（SNP = 2.72E-8）3P25.3（SNP = 2.72E-8）（ghrl; p = 2.72e-8）（grl; p = 2.72e-8）（rs192092592）（rs192092592）（rs192092592）。在TWA中，血清生长素蛋白与GDNF家族受体α（GFRAL）的RNA表达呈负相关，厌食性生长分化因子15（GDF15）的受体（Z-SCORE = -4.288，p = 1.81e-05）。此外，生长素素与核糖体蛋白L36呈正相关（RPL36； Z-SCORE = 4.848，P = 1.25E-06）。结论：我们的发现提供了两个重量调节的主要参与者，Ghrelin System和GDF15/GFRAL-Pathway之间的功能联系的证据。
Objective: Ghrelin is an orexigenic peptide hormone involved in the regulation of energy homeostasis, food intake and glucose metabolism. Serum levels increase anticipating a meal and fall afterwards. Underlying genetic mechanisms of the ghrelin secretion are unknown. Methods: Total serum ghrelin was measured in 1501 subjects selected from the population-based LIFE-ADULT-sample after an overnight fast. A genome-wide association study (GWAS) was performed. Gene-based expression association analyses (transcriptome-wide association study (TWAS)) were done using MetaXcan. Results: In the GWAS, three loci reached genome-wide significance: the WW-domain containing the oxidoreductase-gene (WWOX; p=1.80E-10) on chromosome 16q23.3-24.1 (SNP: rs76823993); the Contactin-Associated Protein-Like 2 gene (CNTNAP2; p=9.0E-9) on chromosome 7q35-q36 (SNP: rs192092592) and the Ghrelin And Obestatin Prepropeptide gene (GHRL; p=2.72E-8) on chromosome 3p25.3 (SNP: rs143729751). In the TWAS, serum ghrelin was negatively associated with RNA expression of the GDNF Family Receptor Alpha Like (GFRAL), receptor of the anorexigenic Growth Differentiation Factor-15 (GDF15), (z-score=-4.288, p=1.81E-05). Furthermore, ghrelin was positively associated with Ribosomal Protein L36 (RPL36; z-score=4.848, p=1.25E-06). Conclusions: Our findings provide evidence of a functional link between two major players of weight regulation, the ghrelin system and the GDF15/GFRAL-pathway.
