Journal
CELL METABOLISM
Volume 31, Issue 6, Pages 1107-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2020.05.007
Keywords
-
Categories
Funding
- NHS Blood and Transplant England - National Institute for Health Research (NIHR)
- NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust)
- Wellcome Trust
- NIHR Blood and Transplant Research Unit in Donor Health and Genomics [NIHR BTRU-2014-10024]
- UK Medical Research Council [MR/L003120/1]
- British Heart Foundation
- Health Data Research UK - UK Medical Research Council, Engineering and Physical Sciences Research Council
- Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government)
- Public Health Agency (Northern Ireland)
- Wellcome [208363/Z/17/Z]
- Medical Research Council
- European Union
- National Institute for Health Research (NIHR)
- Clinical Research Facility, and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- NIHR Cambridge Biomedical Research Centre
- NIHR Senior Investigator Award
- Bernard Wolfe Health Neuroscience Endowment
- Swiss National Science Foundation [P2EZP3_175090, WT098051, WT206194, WT091310]
- Swiss National Science Foundation (SNF) [P2EZP3_175090] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MC_UU_00014/5, MC_UU_12015/1, MC_UU_00007/10, MR/L003120/1, MC_UU_00006/1] Funding Source: UKRI
Ask authors/readers for more resources
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, andZMYM4) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available