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

• Published in: European journal of endocrinology Vol. 184; no. 6; pp. 847 - 856
• Main Authors: Wittekind, Dirk Alexander, Scholz, Markus, Kratzsch, Jürgen, Löffler, Markus, Horn, Katrin, Kirsten, Holger, Witte, Veronica, Villringer, Arno, Kluge, Michael
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.06.2021; Oxford University Press
• Subjects: Adolescent; Adult; Chromosome 3; Chromosome 7; Chromosomes; Clinical Study; Contactin; Energy balance; Female; Food intake; Gene expression; Gene Expression Profiling; Genes; Genome-wide association studies; Genome-Wide Association Study; Genomes; Ghrelin; Ghrelin - blood; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Glucose metabolism; Homeostasis; Humans; Male; Membrane Proteins - genetics; Nerve Tissue Proteins - genetics; Oxidoreductase; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Serum levels; Single-nucleotide polymorphism; Statistical analysis; Transcriptome; Transcriptomes; WW Domain-Containing Oxidoreductase - genetics; Young Adult
• ISSN: 0804-4643; 1479-683X; 1479-683X
• DOI: 10.1530/EJE-20-1220

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 the 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.