Exhaustive Identification of Pleiotropic Loci for Serum Leptin Levels in the NHGRI-EBI Genome-Wide Association Catalog
Résumé
Leptin is an adipokine that regulates energy expenditure and calory intake by acting on the hypothalamic leptin-melanocortin pathway. It has known effects on obesity, inflammation, and neurodevelopment, hence carrying high pleiotropic potential. Using the Genome-Wide Association Study (GWAS) Catalog, we identified the single nucleotide polymorphisms (SNPs) associated with fluctuations of leptin in the blood, which we expanded into wider genetic blocks, and explored their associations and effect sizes with leptin levels. We then investigated the genetic pleiotropy linked with these genomic regions. Starting from 35 GWAS studies on leptin levels with a minimum discovery sample size > 1000 individuals, we selected 25 SNPs reaching genome-wide significance (p < 5.10-8). This led to the aggregation of 15 genetic blocks with SNPs in high linkage disequilibrium with the leptin SNPs. The blocks were also associated with 574 pleiotropic phenotypes, which were then grouped into 22 categories, including the enriched “other adipokines”, “obesity-related”, “inflammation-related”, “cancer-related”, “body fat”, “type-2-diabetes-related”, and “addiction-related” cross-traits. The list of genes overlapping with the genetic blocks was used to map a protein-protein interaction network surrounding leptin with which we identified functional modules enriched in ontological terms such as the leptin-melanocortin pathway, embryogenesis, immunity and transcription regulation. This study extends the genetic architecture behind leptin levels to its wider roles in human physiology by deciphering molecular pathways and gene modules implicated in its end effects.
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