Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription

Publication: Cell Metabolism

Marenne, G., Hendricks, A., Perdikari, A., Bounds, R., Payne, F., Keogh, J., Lelliott, C., Henning, E., Pathan, S., Ashford, S., Bochukova, E., Mistry, V., Daly, A., Hayward, C., Wareham, N., O’Rahilly, S., Langenberg, C., Wheeler, E., Zeggini, E., Farooqi, I. and Barroso, I.

2 June 2020


Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, the researchers identified three genes (PHIPDGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases.

In cells, they showed that PHIP is involved in human energy homeostasis, which has potential diagnostic and therapeutic implications for patients with obesity and developmental delay.

Additionally, they found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies.

Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability.

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