Exome Sequencing Identifies Multiple Genes and Gene-Sets Contributing to Severe Childhood Obesity

Abstract

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome sequencing followed by targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, ZMYM4) with an excess burden in cases of variants (MAF<0.025%) predicted to affect function. In cells, we found that nuclear PHIP (Pleckstrin Homology domain Interacting Protein) directly enhances transcription of Pro-opiomelanocortin (POMC), a neuropeptide which suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. We found an excess burden of in silico deleterious variants (MAF<0.025%) in genes nearest to loci from obesity genome-wide association studies and genes intolerant to loss-of-function, in gene-set analyses. The discovery of genes and gene-sets influencing obesity in a non-fully penetrant manner provides mechanistic insights and has diagnostic and therapeutic implications.