Table 1.

Overview of key genes identified from studies of obesity

Gene	Biology	Other Associated Phenotypes
Identified from genome-wide association studies (GWAS)
Fat mass and obesity-associated gene (FTO) [48–50, 71, 64, 66, 68, 69]	Expressed in hypothalamus, pituitary and adrenal grands Energy homeostasis, regulation of fat mass and body weight Adipogenesis m6A demethylase, reduced m6A ghrelin methylation and increased ghrelin expression	Postnatal mortality Growth retardation T2DM
Melanocortin 4 receptor (MC4R) [38, 40, 41, 51]	Expressed in hypothalamus Acts as a receptor for pro-opiomelanocortin (POMC)-derived peptides to regulate appetite, energy homeostasis and satiety	Monogenic obesity Hyperinsulinemia Hypertriglyceridemia Polyphagia Tall stature T2DM Hypertension
Endosomal/lysosomal Niemann-Pick C1 gene (NPC1) [52, 73–75]	Ubiquitous expression, highest in immune cells and hypothalamus Resides in endosomes and lysosomes and mediates intracellular cholesterol trafficking	Niemann-Pick disease type C Hypertriglyceridemia Coronary artery disease
c-MAF proto-oncogene (MAF) [52, 76, 77, 181]	Ubiquitous expression Developmental and cellular differentiation processes in the immune system, pancreas and adipose tissue Tissue-specific transcriptional regulation of gene expression including insulin and glucagon	Congenital cerulean cataract 4 (CCA4) Chronic obstructive pulmonary disease Lysophosphatidylcholine levels
Phosphotriesterase-related gene (PTER) [52]	Hydrolase activity Biology related to obesity is unknown	Adolescent idiopathic scoliosis Fractures in osteoporosis Height
Prolactin (PRL) [52]	Anterior pituitary hormone Growth regulator with roles in immune cells Essential for lactation	Chronic obstructive pulmonary disease Osteitis deformans
Identified from whole-exome sequencing (WES)
Leptin receptor (LEPR) [38, 41, 57, 58]	Receptor for leptin for regulation of body weight via hypothalamic control to reduce feeding and regulate energy balance Stimulates POMC	Monogenic obesity Pituitary dysfunction Hypothyroidism High rate of childhood infections
Lipoprotein receptor-related protein 2 (LRP2) [59, 182]	Regulation of leptin-melanocortin pathways Appetite regulation and generation of satiety signals in hypothalamic neurons Multi-ligand endocytic receptor, including for leptin	Donnai-Barrow/Facio-oculo-acoustico-renal (DB/FOAR) syndrome Developmental delay Urate levels Renal function and proteinuria Ocular phenotypes
Uncoupling protein 2 (UCP2) [59, 78, 174, 175]	Separate oxidative phosphorylation from ATP Facilitate transfer of anions across inner mitochondrial membranes Regulate energy balance, body weight and thermoregulation Role in response to inflammatory stimuli	Hyperinsulinemia hypoglycemia Hepatomegaly Predictive of lesser weight loss
Dynein axonemal assembly factor 1 (DNAAF1) [59, 183, 184]	Stability of ciliary architecture	Primary Ciliary Dyskinesia (PCD)
Laminin subunit beta 3 (LAMB3) [60, 185]	Basement membrane protein Elevated LAMB3 mRNA levels correlate with BMI In vitro LAMB3 knockdown inhibits adipogenesis	Growth delay Skin abnormalities including epidermolysis bullosa
Pleckstrin homology domain interacting protein (PHIP) [61]	Binds insulin receptor substrate 1 protein and regulates glucose transporter translocation in skeletal muscle Enhances transcription of POMC	Developmental delay Sjögren’s syndrome Hypertension
Diacylglycerol kinase iota (DGKI) [61]	Regulates intracellular diacylglycerol concentrations	Schizophrenia Age-related cognitive decline Retinal degeneration
Zinc-finger-MYM-type-containing 4 (ZMYM4) [61]	Regulation of cell morphology and cytoskeletal organization	Schizophrenia