Genome-wide association and transcriptome analysis suggests total serum ghrelin to be linked with GFRAL

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)) are statistical tests associating genetically predicted expression to a certain trait and 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, the three genes where expression was strongest associated with serum ghrelin levels was the Ribosomal Protein L36 (RPL36; p=1.3E-06, FDR=0.011, positively correlated), AP1B1 (p=1.1E-5, FDR=0.048, negatively correlated) and the GDNF Family Receptor Alpha Like (GFRAL), receptor of the anorexigenic Growth Differentiation Factor-15 (GDF15), (p=1.8E-05, FDR=0.15, also negatively correlated). Conclusions: The three genome-wide significant genetic loci from the GWA and the genes identified in the TWA are functionally plausible and should initiate further research.