Using whole exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, Prof Farooqi’s team in collaboration with Prof Barroso and her team, identified three genes (PHIP, DGKI, and ZMYM4) enriched with deleterious variants in obese cases. PHIP was of particular interest as changes in this gene have been found in children with learning difficulties, some of whom were reported to be overweight. This suggests that PHIP might be a key gene for controlling development and weight.
Further work showed that in cells, nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription, providing a potential mechanism of how PHIP is linked to weight regulation.
In additional analysis focused on groups of genes they found that rare variants predicted to be deleterious were enriched in obese individuals in genes mapping to BMI associated loci from GWAS. This group of 157 genes warrants further investigation in additional obese subjects as this may identify additional genes involved in weight regulation.
The work by Prof Farooqi’s and Prof Barroso’s teams suggests that PHIP should be included in genetic testing recommended in clinical guidelines as part of the assessment of severe childhood obesity, particularly in children with developmental delay.