Genes & Pathways
Browse genes and biological pathways in the GENARCH atlas. Toggle between gene and pathway lists. Population-level summaries for educational use only; not for individual risk assessment.
ACE— Angiotensin-converting enzyme
ACE encodes angiotensin-converting enzyme, a zinc metallopeptidase that converts angiotensin I to angiotensin II and inactivates bradykinin. ACE is central to the renin-angiotensin-aldosterone system (RAAS) regulating blood pressure and fluid homeostasis. The insertion/deletion (I/D) polymorphism in intron 16 associates with circulating ACE activity; D allele confers higher enzyme levels. ACE influences vascular tone, aldosterone release, and cardiac remodeling. Expression is high in lung (vascular endothelium), kidney, and heart. ACE inhibitors are first-line antihypertensives. The gene links genetic variation to hypertension susceptibility and response to RAAS-blocking drugs.
APOE— Apolipoprotein E
APOE encodes apolipoprotein E, a lipid-binding protein that mediates cholesterol and triglyceride transport in the brain and periphery. The epsilon4 allele (APOE4) is the strongest genetic risk factor for late-onset Alzheimer disease, conferring ~3-fold increased risk per copy. APOE influences amyloid-beta aggregation, clearance, and neuroinflammation. In the periphery, APOE modulates LDL metabolism and atherosclerosis. Expression is highest in liver, brain (astrocytes, microglia), and macrophages. APOE has three common isoforms (E2, E3, E4) differing in amino acids 112 and 158. E4 carriers show earlier amyloid deposition and faster cognitive decline.
BDNF— Brain-derived neurotrophic factor
BDNF encodes brain-derived neurotrophic factor, a neurotrophin that supports neuronal survival, synaptic plasticity, and neurogenesis. The Val66Met variant (rs6265) affects activity-dependent secretion and is associated with depression, anxiety, and stress-related phenotypes. BDNF is implicated in the pathophysiology of major depressive disorder and schizophrenia; stress and early adversity interact with genotype. Expression is regulated by exercise, antidepressants, and environmental enrichment.
BRCA1— BRCA1 DNA repair associated
BRCA1 encodes a tumor suppressor protein essential for homologous recombination (HR) DNA double-strand break repair. Germline loss-of-function mutations confer high lifetime risk of breast cancer (up to 72%) and ovarian cancer. BRCA1 forms complexes with PALB2, BRCA2, and RAD51 to promote error-free HR; deficiency leads to genomic instability and reliance on error-prone repair. BRCA1 also regulates transcription, cell cycle checkpoints, and centrosome function. Expression is cell-cycle regulated, peaking in S and G2 phases. Mutations cluster in the RING and BRCT domains. Carriers may have increased sensitivity to DNA-damaging agents including radiation.
BRCA2— BRCA2 DNA repair associated
BRCA2 encodes a tumor suppressor that binds RAD51 and promotes its loading onto single-stranded DNA during homologous recombination. Like BRCA1, germline loss-of-function mutations confer high risk of breast and ovarian cancer; BRCA2 mutations also increase prostate and pancreatic cancer risk. BRCA2 facilitates strand invasion and Holliday junction formation; deficiency causes chromosomal aberrations and sensitivity to crosslinking agents. The gene is cell-cycle regulated and expressed in proliferating tissues. Male BRCA2 carriers have elevated breast cancer risk. Functional domains include the BRC repeats (RAD51 binding) and the DNA-binding domain. PARP inhibitors show efficacy in BRCA2-mutant cancers.
DRD2— Dopamine receptor D2
DRD2 encodes the dopamine D2 receptor, a G protein-coupled receptor that inhibits adenylyl cyclase and modulates dopaminergic signaling in striatum, cortex, and limbic regions. DRD2 is the primary target of antipsychotic drugs; allelic variation influences treatment response and side effects. GWAS have implicated DRD2 and nearby ANKK1 (rs1800497) in schizophrenia, addiction, and Parkinson disease. The receptor exists in long (D2L) and short (D2S) splice variants with distinct signaling properties. Expression is highest in striatum, substantia nigra, and pituitary. DRD2 antagonism underlies antipsychotic efficacy but also causes extrapyramidal and metabolic side effects.
EGFR— Epidermal growth factor receptor
EGFR encodes the epidermal growth factor receptor, a receptor tyrosine kinase that binds EGF and related ligands to activate RAS-RAF-MAPK and PI3K-AKT signaling. Somatic EGFR mutations (especially exon 19 deletions and L858R) drive a subset of non-small cell lung cancers, particularly in never-smokers and East Asians. These mutations confer sensitivity to EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, osimertinib). EGFR overexpression occurs in many epithelial cancers. The receptor dimerizes upon ligand binding and autophosphorylates. Expression is highest in epithelial tissues. Germline EGFR variants may modify lung cancer risk. Resistance to TKIs commonly arises through T790M or MET amplification.
FTO— Fat mass and obesity-associated protein
FTO encodes fat mass and obesity-associated protein, an alpha-ketoglutarate-dependent dioxygenase that demethylates nucleic acids. The FTO locus harbors the strongest common genetic association with obesity (e.g., rs9939609); risk alleles confer ~3 kg higher body weight per copy. FTO influences energy balance through effects on appetite, food preference, and possibly energy expenditure. Risk variants regulate expression of neighboring genes (RPGRIP1L, IRX3) rather than FTO itself, via long-range regulatory elements. FTO is widely expressed, with high levels in brain (hypothalamus), adipose tissue, and muscle. The gene links genetic susceptibility to obesogenic environmental exposures.
GSTP1— Glutathione S-transferase pi 1
GSTP1 encodes glutathione S-transferase pi 1, which conjugates glutathione to electrophilic compounds and reactive oxygen species, detoxifying oxidative stress. The Ile105Val (rs1695) polymorphism alters enzyme activity and has been widely studied in gene–environment interactions with air pollution, tobacco smoke, and other oxidative exposures. GSTP1 variants modify associations between PM2.5 and asthma, and smoking and lung function. Expression is high in lung, liver, and epithelial tissues.
HLA-DRB1— Major histocompatibility complex, class II, DR beta 1
HLA-DRB1 encodes the beta chain of HLA-DR, an MHC class II molecule that presents exogenous antigens to CD4+ T cells. Specific HLA-DRB1 alleles (e.g., shared epitope: *01, *04, *10) confer strong genetic risk for rheumatoid arthritis; other alleles associate with multiple sclerosis and other autoimmune diseases. The shared epitope alleles present arthritogenic peptides and shape the T cell repertoire. HLA-DRB1 is highly polymorphic with hundreds of alleles. Expression is restricted to antigen-presenting cells: B cells, dendritic cells, macrophages. Risk alleles may influence thymic selection, peptide binding, or T cell activation. The HLA region shows the strongest genetic associations in autoimmune disease.
IL33— Interleukin 33
IL33 encodes interleukin-33, a dual-function cytokine and nuclear factor belonging to the IL-1 family. IL-33 functions as an epithelial alarmin: it is constitutively expressed in barrier tissues (lung, skin, gut) and released upon cell damage or stress, acting as a danger signal to activate innate and adaptive immune cells. Full-length IL-33 binds the ST2 (IL1RL1) receptor on group 2 innate lymphoid cells (ILC2s), mast cells, Th2 lymphocytes, and eosinophils, driving type 2 immunity. Proteolytic cleavage by allergens or inflammatory proteases generates mature forms with enhanced activity. Asthma-associated GWAS variants regulate IL33 expression through an enhancer-blocking element ~2.3 kb upstream, with differential OCT-1 (POU2F1) binding. IL-33 is upregulated by PM2.5, allergens, and viral infections, positioning it at the interface of environmental exposure and genetic susceptibility in asthma.
LDLR— LDL receptor
LDLR encodes the low-density lipoprotein receptor, a cell-surface glycoprotein that binds and internalizes LDL cholesterol particles. The receptor mediates endocytosis of cholesterol-carrying lipoproteins, regulating plasma cholesterol homeostasis. Mutations in LDLR cause familial hypercholesterolemia (FH), characterized by severely elevated LDL-C and premature coronary artery disease. GWAS have identified common variants near LDLR that modestly affect LDL-C levels and CAD risk. The gene is transcriptionally regulated by SREBP-2 in response to cellular cholesterol demand. Expression is highest in liver, adrenal cortex, and steroidogenic tissues.
LEP— Leptin
LEP encodes leptin, an adipokine secreted by adipose tissue that signals energy sufficiency to the hypothalamus via the leptin receptor (LEPR). Leptin suppresses appetite and promotes energy expenditure through melanocortin and other pathways. Rare LEP mutations cause severe early-onset obesity; common variants contribute to polygenic obesity. Circulating leptin correlates with fat mass; diet and physical activity modulate levels. Leptin resistance in obesity is a therapeutic target.
MC4R— Melanocortin 4 receptor
MC4R encodes the melanocortin 4 receptor, a G protein-coupled receptor in the hypothalamic leptin-melanocortin pathway that regulates energy balance and appetite. MC4R is activated by alpha-MSH (from POMC neurons) and inhibited by AgRP; activation suppresses food intake and increases energy expenditure. Loss-of-function mutations cause severe early-onset obesity; common variants (e.g., rs17782313 near MC4R) associate with BMI and obesity in GWAS. MC4R is expressed in paraventricular and other hypothalamic nuclei. The receptor couples to Gs and activates cAMP; mutations disrupt signaling through varied mechanisms. MC4R agonists are emerging as anti-obesity therapeutics.
MTHFR— Methylenetetrahydrofolate reductase
MTHFR encodes methylenetetrahydrofolate reductase, which converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for homocysteine remethylation. The C677T variant (rs1801133) reduces enzyme activity and raises homocysteine, especially when folate intake is low. Associated with cardiovascular disease, neural tube defects, and (controversially) depression. Folate and B-vitamin status are key environmental modifiers; gene–nutrient interactions are well documented.
PCSK9— Proprotein convertase subtilisin/kexin type 9
PCSK9 encodes proprotein convertase subtilisin/kexin type 9, a serine protease that binds the LDL receptor and targets it for lysosomal degradation. By reducing hepatic LDLR abundance, PCSK9 raises plasma LDL cholesterol levels. Gain-of-function mutations cause autosomal dominant hypercholesterolemia, while loss-of-function variants confer lower LDL-C and reduced coronary artery disease risk. PCSK9 inhibitors (evolocumab, alirocumab) have emerged as potent LDL-lowering therapies. The gene is expressed primarily in liver, intestine, and kidney. GWAS consistently implicate PCSK9 in LDL-C and CAD susceptibility.
PPARG— Peroxisome proliferator-activated receptor gamma
PPARG encodes a nuclear receptor that regulates adipocyte differentiation, lipid metabolism, and insulin sensitivity. The Pro12Ala variant (rs1801282) is associated with lower T2D risk and improved insulin sensitivity. PPARG is the target of thiazolidinediones (TZDs). It is central to metabolic and inflammatory pathways; diet and obesity strongly interact with genetic variation. Expression is highest in adipose tissue and macrophages.
SERPINA1— Alpha-1 antitrypsin
SERPINA1 encodes alpha-1 antitrypsin (A1AT), a serine protease inhibitor that protects lung tissue from neutrophil elastase. The severe Z allele (Glu342Lys) causes protein misfolding and accumulation in hepatocytes, leading to deficiency in lung and liver disease. A1AT deficiency is a major genetic cause of early-onset emphysema and COPD, particularly in smokers. Normal A1AT inhibits neutrophil elastase; deficiency permits unchecked protease activity and alveolar destruction. Expression is hepatic; protein is secreted into serum and reaches lung via circulation. PiZZ homozygotes have ~10-20% of normal A1AT levels. Cigarette smoke oxidatively inactivates A1AT, exacerbating the protease-antiprotease imbalance.
SLC6A4— Solute carrier family 6 member 4
SLC6A4 encodes the serotonin transporter (5-HTT), which reuptakes serotonin from the synaptic cleft and terminates serotonergic signaling. The promoter polymorphism 5-HTTLPR (short vs long) modulates transporter expression and has been extensively studied in depression, stress response, and suicidal behavior. Short allele carriers show exaggerated amygdala reactivity and may be more vulnerable to depression following adversity. SLC6A4 is the target of SSRIs. Expression is highest in raphe nuclei, platelets, and placenta. Genetic variation influences SSRI response. The gene-denvironment interaction (5-HTTLPR × stress → depression) has been debated but remains influential in psychiatric genetics.
SOD2— Superoxide dismutase 2, mitochondrial
SOD2 encodes manganese superoxide dismutase, a mitochondrial enzyme that converts superoxide to hydrogen peroxide and protects against oxidative stress. The Ala16Val (rs4880) polymorphism affects mitochondrial targeting and activity. SOD2 is implicated in aging, cardiovascular disease, and conditions driven by oxidative stress; air pollution and smoking increase oxidative burden and may interact with genotype. Expressed in metabolically active tissues.
TCF7L2— Transcription factor 7-like 2
TCF7L2 encodes transcription factor 7-like 2, a nuclear effector of the Wnt signaling pathway that regulates gene expression in pancreatic beta cells, intestinal enteroendocrine cells, and hepatic tissues. The gene harbors the strongest common genetic risk variant for type 2 diabetes (rs7903146), with the T allele conferring ~40% increased risk per copy. TCF7L2 influences insulin secretion, incretin response, and hepatic glucose production. Risk variants associate with impaired beta cell function and blunted glucagon-like peptide-1 (GLP-1) response. Expression is highest in intestine, pancreas, and brain. The Wnt/TCF7L2 axis modulates developmental and metabolic gene networks.
TP53— Tumor protein p53
TP53 encodes p53, a critical tumor suppressor that coordinates cellular responses to DNA damage, oncogenic stress, and other insults. p53 arrests the cell cycle, promotes DNA repair, or induces apoptosis depending on context. Germline TP53 mutations cause Li-Fraumeni syndrome with high cancer risk. Somatic TP53 mutations occur in >50% of human cancers, including breast and lung. p53 regulates hundreds of targets including p21, PUMA, and Bax. The protein is normally short-lived; stress stabilizes it. MDM2 targets p53 for degradation. Expression is ubiquitous. TP53 status influences therapeutic response; mutant p53 can acquire gain-of-function properties that promote metastasis.