Table 1.
Overview of all genes implicated in severe and early-onset obesity
| Gene symbol, name, Gene ID | Location (human, GRCh38/hg38) chr: start…end position | Species in which naturally occurring mutations cause obesity | Tissue expression | Nearby GWAS-identified locus (index SNP) | Role in body-weight regulation |
|---|---|---|---|---|---|
| ADCY3, adenylate cyclase, Gene ID: 109 | 2: 24,819,168…24,920,236 | Humans | Primary cilia of cells | rs6545814 | Disruption of primary cilia in neurons known to influence energy balance67; some evidence of a specific link to the correct function of MC4R67,156 |
| AGRP, agouti-related protein, Gene ID: 181 | 16: 67,482,571…67,483,547 | – | Neurons in the arcuate nucleus of the hypothalamus | – | Endogenous antagonist of MC4R, to which it binds to increase food intake92,94 |
| BDNF, brain-derived neurotrophic factor, Gene ID: 627 | 11: 27,654,893…27,722,030 | Humans | Brain | rs925946 | Probably via its role in regulating neuronal synaptic plasticity111,115 |
| KSR2, kinase suppressor of Ras2, Gene ID: 283455 | 12: 117,453,012…117,968,990 | Humans | Wide expression throughout the body | rs56214831 | Influences both energy intake and expenditure, possibly via interaction with AMPK168 |
| LEP, leptin, Gene ID: 3952 | 7: 128,241,201…128,257,629 | Humans and mice | Fat | rs10487505 | Circulates in proportion to fat mass21,90, and turns on the neuroendocrine starvation response when circulating levels drop below a minimum threshold91 |
| LEPR, leptin receptor, Gene ID: 3953 | 1: 65,420,652…65,641,559 | Humans and mice | The long ‘signalling’ form is expressed widely in the brain | rs11208659 | Cognate receptor for leptin, mediating its downstream neuroendocrine functions16,22 |
| MC4R, melanocortin 4 receptor, Gene ID: 4160 | 18: 60,371,062…60,372,775 | Humans, pigs and blind Mexican cavefish | Central nervous system | rs17782313 | Binds melanocortin peptides and AGRP to mediate appetitive behaviour92 and autonomic output169 |
| MRAP2, melanocortin receptor accessory protein 2, Gene ID: 112609 | 6: 84,032,621…84,146,278 | Humans | Wide expression throughout the body, but highest in the brain | – | An accessory protein that plays a role in trafficking MC4R to the cell surface99 |
| NTRK2, neurotrophic receptor tyrosine kinase 2, Gene ID: 4915 | 9: 84,668,458…85,027,070 | Humans | Brain | rs10868215 | Cognate receptor for BDNF, mediating its downstream effects on synaptic plasticity116 |
| PCSK1, proprotein convertase subtilisin/kexin type 1, Gene ID: 5122 | 5: 96,390,333…96,433,248 | Humans | Endocrine organs, with highest expression in the brain | rs6235 | Encodes one of the prohormone convertases required for processing POMC93 |
| PHIP, pleckstrin homology domain interacting protein, Gene ID: 55023 | 6: 78,934,419…79,078,294 | Humans | Widely expressed | – | Regulates transcription of POMC98 |
| POMC, pro-opiomelanocortin, Gene ID: 5443 | 2: 25,160,860…25,168,580 | Humans and Labrador retriever dogs | Hypothalamus, nucleus tractus solitaris, pituitary, skin, adrenal glands and numerous other tissues | rs6545975 | Complex pro-polypeptide that is processed into melanocortin peptides that signal to MC4R in the brain27,93 |
| SH2B1, SH2B adaptor protein 1 Gene ID: 25970 | 16: 28,846,606…28,874,205 | Humans | Widely expressed | rs7498665 | A signalling molecule downstream of the leptin receptor97 |
| SIM1, SIM bHLH transcription factor 1, Gene ID: 6492 | 6: 100,385,009…100,464,929 | Humans | Hypothalamus, kidney and fat | rs6907240 | A transcription factor crucial for the proper development of the paraventricular nucleus and hence appropriate expression of MC4R, among other genes100 |
AMPK, AMPK-activated kinase; bHLH. basic helix–loop–helix; GWAS, genome-wide association study.