Diseases
Browse diseases in the GENARCH atlas with population-level genetic architecture, exposure modifiers, and tissue context. This information is for educational purposes and does not imply individual risk.
Alzheimer's Disease
Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive neurodegeneration, amyloid-beta plaques, and neurofibrillary tau tangles. Pathophysiology involves amyloid cascade, tau pathology, neuroinflammation, synaptic loss, and eventual neuronal death. Onset is typically late life; early-onset familial AD (5–10%) is caused by rare mutations in APP, PSEN1, and PSEN2. Genetic susceptibility in late-onset AD: heritability is ~60–80%; SNP-based h² is ~0.07. APOE ε4 is the strongest common genetic risk factor (3–15-fold depending on copy number). Over 40 susceptibility loci have been identified. Vascular, metabolic, and lifestyle factors modify risk. Disease begins decades before clinical symptoms; preventive interventions may be most effective in mid-life and earlier.
Asthma
Asthma is a heterogeneous chronic respiratory disease characterized by variable airflow obstruction, bronchial hyperresponsiveness (BHR), and airway inflammation. The disease sits within the atopic march, where allergic sensitization in early life (food allergy, atopic dermatitis) often precedes allergic rhinitis and asthma development. Pathophysiologically, asthma involves T-helper 2 (Th2)–mediated inflammation, eosinophilic infiltration, goblet cell hyperplasia, and airway remodeling. The phenotypic spectrum ranges from mild intermittent disease to severe therapy-resistant asthma, with distinct endotypes including type 2–high (eosinophilic, allergen-driven) and type 2–low (neutrophilic or paucigranulocytic) presentations. Genetic susceptibility contributes substantially: twin studies estimate heritability at ~60–80%, while SNP-based heritability (h²) is ~0.15–0.20, reflecting the polygenic architecture. Prevalence varies globally (5–20%), with higher rates in industrialized nations and urban settings. Asthma onset frequently occurs in childhood or adolescence, making it highly relevant to the 10–24 age group—a period when disease trajectory, medication adherence, and environmental exposures (including smoking initiation and occupational exposures) critically shape long-term outcomes.
Atopic Dermatitis
Atopic dermatitis (eczema) is a chronic inflammatory skin disease characterized by pruritus, erythema, and barrier dysfunction. It is a component of the atopic march (often preceding asthma and allergic rhinitis). Th2 skewing, filaggrin (FLG) deficiency, and epithelial barrier defects are central. Heritability ~75%; SNP-based h² ~0.15. Key genes include FLG (loss-of-function), IL4/IL13 (Th2), and TSLP. Allergens, irritants, climate, and stress trigger flares; microbiome and diet may modify risk.
Bipolar Disorder
Bipolar disorder is a mood disorder characterized by recurrent episodes of mania or hypomania and depression. Pathophysiology involves dysregulation of monoaminergic and glutamatergic systems, circadian rhythm disruption, and neuroplasticity deficits. Heritability is high (~70–80%); SNP-based h² ~0.25. Key loci include CACNA1C (calcium signaling), ANK3 (ankyrin-G), and genes in dopamine and circadian pathways. Stress, sleep deprivation, and substance use are environmental triggers. Adolescence and early adulthood are peak onset periods.
Breast Cancer
Breast cancer is the most common malignancy in women globally, arising from ductal or lobular epithelium. Pathophysiology involves dysregulated cell proliferation, genomic instability, and hormone receptor signaling (ER, PR, HER2). Subtypes differ in prognosis and therapy. Genetic susceptibility is substantial: heritability from twin studies is ~30%; SNP-based h² is ~0.08–0.15. Rare high-penetrance mutations (BRCA1, BRCA2, TP53) account for ~5–10% of cases; common variants explain additional variance. Key genes include BRCA1/BRCA2 (DNA repair), TP53 (tumor suppressor), and FGFR2 (receptor signaling). Hormonal, reproductive, and lifestyle factors interact with genetic risk. Early menarche, late menopause, nulliparity, and obesity modify risk. Adolescence is a sensitive window for breast development and carcinogen exposure.
Colorectal Cancer
Colorectal cancer (CRC) encompasses malignancies arising from the colon or rectum, with adenocarcinoma comprising the majority of cases. Pathogenesis involves the adenoma-carcinoma sequence: accumulated genetic and epigenetic alterations drive progression from normal epithelium through adenomatous polyps to invasive carcinoma. Inherited susceptibility contributes ~35% of CRC risk; major genes include APC (familial adenomatous polyposis), MLH1/MSH2 (Lynch syndrome), and numerous GWAS-identified loci affecting cell-cycle, Wnt signaling, and inflammatory pathways. Diet and the gut microbiome are major environmental modifiers—red meat, processed foods, and low fiber intake increase risk, while the gut microbiota influences inflammation, metabolite production, and DNA damage. Adolescent relevance is emerging: diet quality and obesity established during 10–24 years may shape microbiome composition and epigenetic programming that influences later CRC susceptibility. Early-onset CRC is increasing, highlighting the importance of understanding G×E interactions in younger populations.
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by airflow limitation, emphysema, and chronic bronchitis. Pathophysiology involves chronic inflammation, protease–antiprotease imbalance, oxidative stress, and airway remodeling. Alpha-1 antitrypsin deficiency (SERPINA1) causes ~1% of cases but illuminates mechanism. Genetic susceptibility: heritability is ~40–70%; SNP-based h² is ~0.12. Key genes include SERPINA1 (protease inhibitor), HHIP (hedgehog signaling, lung development), FAM13A, and loci near MMP12. Cigarette smoking is the dominant environmental cause; gene–smoking interactions are well-established. Only ~15–20% of smokers develop COPD, highlighting genetic susceptibility. Air pollution and occupational exposures contribute. Early-life lung development and adolescent smoking shape disease trajectory.
Coronary Artery Disease
Coronary artery disease (CAD) is the leading cause of death globally, characterized by atherosclerosis—the progressive buildup of fatty plaques in coronary arteries that supply the heart. Pathophysiology involves endothelial dysfunction, lipid accumulation, chronic inflammation, plaque rupture, and thrombosis. CAD manifests as angina, myocardial infarction, or sudden cardiac death. Genetic susceptibility contributes substantially: heritability estimates range from 40–60% based on twin and family studies. SNP-based heritability (h²) is approximately 0.13–0.16, reflecting highly polygenic architecture. Key Mendelian genes (LDLR, APOB, PCSK9, LPA) illuminate cholesterol metabolism pathways; common-variant GWAS have identified over 300 loci. Prevalence increases with age and varies by population and lifestyle. Modifiable risk factors—hypertension, dyslipidemia, smoking, diabetes, obesity, physical inactivity, and poor diet—interact with genetic predisposition. Early-life and adolescent exposures shape lifelong cardiovascular risk trajectories.
Hypertension
Hypertension (essential arterial hypertension) is a chronic condition characterized by sustained elevation of blood pressure (≥130/80 mmHg). It is the leading modifiable risk factor for cardiovascular disease, stroke, and chronic kidney disease worldwide. Pathophysiology involves complex interactions between renal sodium handling, the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system overactivity, vascular remodeling, and endothelial dysfunction. Genetic factors contribute substantially, with twin studies estimating heritability at 30–50% and SNP-based heritability ~0.15–0.25. The disease exhibits strong gene–environment interactions: high sodium intake amplifies genetic susceptibility in salt-sensitive individuals, while psychosocial stress and obesity modulate both onset and severity. Adolescents represent a critical window—early-onset hypertension tracks into adulthood, and blood pressure trajectories established in the 10–24 age range predict long-term cardiovascular risk. Lifestyle factors (diet, physical activity, stress) during adolescence can modify epigenetic programming and disease trajectory.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) comprises Crohn disease and ulcerative colitis, chronic disorders of the gastrointestinal tract with dysregulated immune response to gut microbiota. Pathophysiology involves barrier dysfunction, innate and adaptive immunity, and microbiome interactions. Heritability ~50–60%; SNP-based h² ~0.25. Over 200 loci identified; key genes include NOD2, IL23R, ATG16L1, and IRGM. Diet, smoking (divergent effects in CD vs UC), antibiotics, and stress modify risk.
Ischemic Stroke
Ischemic stroke results from occlusion of cerebral arteries, causing focal brain ischemia and infarction. Etiologic subtypes include large-artery atherosclerosis, cardioembolism, small-vessel disease, and other causes. Heritability ~30–40%; SNP-based h² ~0.12. Key loci include PITX2 (atrial fibrillation), HDAC9 (large-vessel), and genes in blood pressure and lipid pathways. Hypertension, smoking, diabetes, and obesity are major modifiable risk factors; they interact with genetic susceptibility.
Lung Cancer
Lung cancer encompasses carcinomas of the lung, predominantly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Tobacco smoking is the principal environmental cause, accounting for ~85% of cases; the smoking–genetics interaction is among the best-characterized gene–environment relationships in oncology. Genetic susceptibility modifies both smoking initiation (nicotine dependence) and lung cancer risk among smokers. Key loci include CHRNA5/CHRNA3 (nicotinic acetylcholine receptors influencing smoking behavior and carcinogen susceptibility), TP53, and EGFR (driver mutations in adenocarcinoma). SNP heritability for lung cancer is modest (~0.05) but increases when considering smoking-adjusted models. Adolescent relevance is significant: smoking initiation typically occurs before age 24; genetic variants in CHRNA5 influence both nicotine dependence and lung cancer risk, creating a dual pathway. Never-smoker lung cancer has distinct genetics (stronger EGFR, weaker smoking loci) and rising incidence in some populations.
Major Depressive Disorder
Major depressive disorder (MDD) is a common mental disorder characterized by persistent low mood, anhedonia, fatigue, and impaired functioning, often with recurring episodes. Neurobiological mechanisms involve dysregulation of monoaminergic systems (serotonin, norepinephrine, dopamine), hypothalamic-pituitary-adrenal (HPA) axis hyperactivation, neuroinflammation, and impaired neuroplasticity. Genetic factors contribute ~37% of variance; SNP heritability ~0.08–0.15, reflecting high polygenicity and substantial environmental influence. Key candidate genes include SLC6A4 (serotonin transporter) and BDNF (brain-derived neurotrophic factor), both implicated in stress response and neural plasticity. Gene–environment interactions are central: childhood adversity and chronic psychosocial stress amplify genetic susceptibility, particularly in 5-HTTLPR and BDNF Val66Met carriers. Adolescence is a critical vulnerability window—onset peaks in late adolescence/early adulthood, and stress exposure during 10–24 years may have lasting effects on HPA axis and neural circuitry.
Multiple Sclerosis
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system, characterized by inflammation, demyelination, axonal damage, and progressive disability. Pathophysiology involves T-cell-mediated autoimmune attack on myelin and oligodendrocytes, with contributions from B cells, microglia, and innate immunity. Genetic susceptibility is substantial—twin concordance ~25%, SNP heritability ~0.25–0.30. The HLA-DRB1*15:01 allele is the strongest genetic risk factor, conferring ~3-fold increased risk. Non-HLA loci implicate immune regulation, vitamin D metabolism, and neuronal resilience. Environmental factors are critical: low vitamin D (from UV/sun exposure and diet), Epstein-Barr virus infection, and smoking amplify risk. Adolescence and young adulthood represent the peak period for disease onset—age 15–24 is when many individuals experience first symptoms. Vitamin D status and EBV seroconversion during this window may be particularly consequential for MS development.
Obesity
Obesity is a multifactorial condition characterized by excess adipose tissue accumulation, with body mass index (BMI) ≥30 kg/m² as a common threshold. Pathophysiology involves energy balance dysregulation, leptin–melanocortin signaling, gut–brain axis, adipose biology, and neuroendocrine pathways. Obesity increases risk for type 2 diabetes, cardiovascular disease, cancer, and musculoskeletal disorders. Genetic susceptibility is substantial: heritability for BMI is ~40–70%; SNP-based h² is ~0.21. Over 900 loci have been identified. Key genes include FTO (energy balance, hypothalamic regulation), MC4R (melanocortin-4 receptor, appetite), and loci in gut–brain axis (LEP, LEPR, POMC). Diet, physical activity, built environment, and psychosocial factors interact with genetic risk. Epigenetic programming in early life may influence susceptibility. Adolescence is a critical period for establishing weight trajectory.
Psoriasis
Psoriasis is a chronic immune-mediated skin disease characterized by hyperproliferation of keratinocytes, epidermal thickening, and inflammatory infiltrate. IL-23/Th17 axis is central; TNF and NF-κB pathways are therapeutic targets. Heritability ~60–70%; SNP-based h² ~0.28. Key genes include HLA-C*06:02, IL23R, and genes in the IL-23/Th17 pathway. Trauma, infection, stress, and medications can trigger flares. Comorbidities include psoriatic arthritis, cardiovascular disease, and metabolic syndrome.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by symmetric inflammatory polyarthritis, joint destruction, and systemic manifestations. Pathophysiology involves autoimmune attack on synovium, with HLA-DRB1 shared epitope, citrullinated peptide recognition, and TNF/IL-6–driven inflammation. Seropositive RA (RF and/or anti-CCP) has stronger genetic component than seronegative. Heritability is ~60%; SNP-based h² is ~0.13. HLA-DRB1 contributes ~30% of genetic variance. Key genes include HLA-DRB1 (antigen presentation), PTPN22 (T-cell signaling), and loci in TNF pathway. Smoking, particularly in HLA-DRB1 carriers, dramatically increases anti-CCP–positive RA risk via citrullination. Infections, obesity, and reproductive factors may modify risk. Early diagnosis and DMARD therapy prevent joint damage.
Schizophrenia
Schizophrenia is a severe psychiatric disorder characterized by positive symptoms (hallucinations, delusions), negative symptoms (avolition, anhedonia), and cognitive impairment. Pathophysiology involves dopamine dysregulation, glutamate hypofunction, neurodevelopmental abnormalities, and neuroinflammation. Onset typically occurs in late adolescence or early adulthood (ages 15–25). Genetic susceptibility is very high: heritability from twin studies is ~80%; SNP-based h² is ~0.24. Over 200 susceptibility loci have been identified. Key genes include DRD2 (dopamine receptor), CACNA1C (calcium channel), and C4A (complement, synaptic pruning). Cannabis use, urban residence, childhood adversity, and migration are environmental risk factors. Gene–environment interactions are active areas of research. Early intervention during prodromal phase may improve outcomes.
Type 2 Diabetes
Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance and progressive beta-cell dysfunction, leading to chronic hyperglycemia. Pathophysiology involves impaired glucose uptake in muscle and adipose tissue, dysregulated hepatic glucose output, and insufficient insulin secretion. Complications include retinopathy, nephropathy, neuropathy, and cardiovascular disease. Genetic susceptibility is substantial: heritability estimates range from 30–70% depending on study design and population. SNP-based heritability (h²) is approximately 0.18–0.25. Over 400 susceptibility loci have been identified; key genes include TCF7L2 (Wnt signaling, beta-cell function), SLC30A8 (zinc transport, insulin secretion), PPARG (adipocyte differentiation, insulin sensitivity), and FTO (energy balance, obesity). T2D is highly modifiable by lifestyle; diet, physical activity, and obesity interact strongly with genetic risk. Onset is increasingly occurring in adolescence and young adulthood.