英国埃克塞特大学Inês Barroso、剑桥大学I. Sadaf Farooqi等研究人员，合作利用外显子组测序鉴定出导致严重儿童肥胖的基因和基因集。这一研究成果于2020年6月2日发表在《细胞—代谢》上。

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

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

Issue&Volume: 2020/06/02

Abstract: 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, 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.

DOI: 10.1016/j.cmet.2020.05.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30246-1