We recently identified three genes called PHIP, DGKI, ZMYM4 which may play an important role in controlling a person’s weight.
In collaboration with Professor Inês Barroso (University of Exeter Medical School) we compared hundreds of genes in 2,737 severely obese children and 6,704 healthy volunteers. We found that while some genetic changes were found in both overweight and normal weight people, for 3 genes, there were more changes predicted to lead to faulty genes in overweight people than in healthy volunteers. This suggested that these genes (called PHIP, DGKI, ZMYM4) might be playing an important role in controlling a person’s weight.
One of the genes called PHIP was particularly interesting because changes in this gene have been found in children with learning difficulties, some of whom were reported to be overweight. Together this work suggested that PHIP might be a key gene for controlling both development and weight.
We then performed experiments to explore the potential ways in which PHIP might regulate weight. We found that inside a cell, PHIP acts to switch on another gene called POMC, which suppresses appetite after a meal. If PHIP is working correctly, it boosts the POMC signal which makes people feel full. When we tested the changes in the PHIP gene found in overweight people, we found these changes stopped the PHIP gene from working correctly, and lowered the amount of POMC. Lower levels of POMC are known to cause weight problems in some children, so this work provides a potential explanation for the link between the PHIP gene and weight problems.
In additional analyses, we found 157 genes which collectively contained more changes predicted to lead to faulty genes in the overweight individuals compared to healthy volunteers. In the future, studying this group of genes in additional overweight people will be important and may lead to new discoveries of genes involved in weight regulation.