全基因组关联和转录组分析揭示血清ghrelin与GFRAL相关
Genome-wide association and transcriptome analysis reveals serum ghrelin to be linked with GFRAL
摘要：
目的：Ghrelin是一种促食欲肽类激素，参与能量平衡、食物摄取和糖代谢的调节。血清水平在进餐前升高，进餐后下降。胃饥饿素分泌的潜在遗传机制尚不清楚。方法：从基于人群的LIFE-ADRESS样本中选择1501名受试者，在禁食过夜后测定血清总ghrelin。进行了全基因组关联研究（GWAS）。使用MetaXcan进行基于基因的表达关联分析（全转录组关联研究（TWAS））。结果如下：在GWAS中，三个位点达到全基因组意义：包含氧化还原酶基因的WW-domain（WWOX; p=1.80E-10）位于染色体16q23.3-24.1（SNP：rs76823993）;接触蛋白相关蛋白样2基因（CNTNAP 2; p=9.0E-9）（SNP：rs 192092592）和染色体3p25.3（SNP：rs 143729751）上的Ghrelin和Obestatin前肽基因（GHRL; p=2.72E-8）。在TWAS中，血清生长素释放肽与GDNF家族受体α样（GFRAL）、促凋亡生长分化因子-15（GDF 15）的受体的RNA表达负相关（z-评分=-4.288，p=1.81E-05）。此外，生长素释放肽与核糖体蛋白L36正相关（RPL 36; z-评分=4.848，p=1.25E-06）。结论：我们的研究结果提供了两个主要的体重调节参与者，ghrelin系统和GDF 15/GFRAL通路之间的功能联系的证据。
英文摘要：
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.
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