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

Gaëlle Marenne,Aliki Perdikari,Stephen O’Rahilly,Nicholas J Wareham,Sofie Ashford,Rebecca Bounds,Inês Barroso,Vanisha Mistry,I Sadaf Farooqi,Claudia Langenberg,Eleftheria Zeggini,Eleanor Wheeler,Julia M Keogh,Saad Pathan,Caroline Hayward,Allan Daly,Audrey E Hendricks,Christopher J Lelliott,Elena G Bochukova,Elana Henning,Felicity Payne

doi:10.1016/j.cmet.2020.05.007

Abstract

SummaryObesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that 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. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we 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.

Highlights

The rising prevalence of obesity is largely driven by the consumption of high-calorie foods and reduced levels of physical activity at work and in leisure time, which contribute to sustained positive energy balance and weight gain
Rare Variants Implicate Three New Genes in Human Energy Homeostasis Here, we studied a cohort of European ancestry individuals with severe childhood-onset obesity (SCOOP) in whom known causes of monogenic obesity, such as congenital leptin deficiency and melanocortin 4 receptor (MC4R) mutations, had been excluded (STAR Methods)
Children were recruited into the cohort if they had a body mass index (BMI) standard deviation score (BMI standard deviation scores (SDS)) greater than three and age of onset below 10 years (Wheeler et al, 2013) (STAR Methods)

Summary

Introduction

The rising prevalence of obesity is largely driven by the consumption of high-calorie foods and reduced levels of physical activity at work and in leisure time, which contribute to sustained positive energy balance and weight gain. Candidate gene studies led to the identification of very rare variants that cause monogenic forms of severe obesity mostly by impacting the function of proteins involved in the central leptin-melanocortin pathway (Doche et al, 2012; O’Rahilly and Farooqi, 2008; Saeed et al, 2018; van der Klaauw and Farooqi, 2015) These findings have had diagnostic value for patients and have paved the way for stratified therapy as seen with the treatment of congenital leptin deficiency by recombinant leptin (Farooqi et al, 1999) and of POMC and LEPR deficiency by the melanocortin 4 receptor (MC4R) agonist setmelanotide (Clement et al, 2018; Ku€hnen et al, 2016)

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