Identifying genetic overlaps in obesity and metabolic disorders unlocking unique and shared mechanistic insights.

Abstract

Objective: Obesity has a high heritability and frequently co-occurs with metabolic disorders, indicating shared genetic susceptibility. The underlying causative genes and biological mechanisms of obesity and metabolic disorders remain predominantly elusive.

Methods: The FinnGen R11 dataset, including over 450,000 subjects, was employed in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 eQTls dataset to conduct cross-tissue transcriptome association studies, Functional Summary-based Imputation in single tissues, and Gene Analysis combined with Multimarker Analysis of Genomic Annotation, respectively, for identifying distinct and shared genetic architectures of obesity and metabolic disorders. We also employed RHOGE to ascertain the genetic correlation and putative causal directions between them. Subsequent Mendelian randomization, colocalization analyses, and other cell and tissue enrichment analyses were employed to enhance our understanding of the functional implications of these susceptibility genes.

Results: A total of 35 genes were identified as obesity susceptibility and 10 genes linked to metabolic disorder susceptibility. Of these, three genes (MCM6, MAPRE3 and UBXN4) were identified as being shared. Mendelian randomization and colocalization analyses revealed the three shared genes have causal associations with obesity and metabolic disorders and serve as independent signals. Subsequent analyses indicated MCM6 may influence obesity and metabolic disorder risk by regulating DNA replication, cell proliferation, and interactions with chemical responses. MAPRE3 may confer protective effects against obesity and metabolic disorders through PAK Pathway, while UBXN4 may involve in regulating cholesterol metabolism.

Conclusion: Our study provides insight into the novel shared genetic mechanism between obesity and metabolic disorders and identifies potential targets for pharmacological intervention.