Overview of
Complex Diseases

An overview of complex diseases, including the genetic and environmental factors involved and the treatment strategies being investigated


What Are Complex Diseases?

Complex diseases are disorders caused by the combinatorial effect of genetic, environmental, and lifestyle factors, which involve multiple molecular networks1,2

  • Complex diseases often aggregate within families but show no clear pattern of inheritance3,4
  • Inheriting disease-associated genes predispose an individual to potentially developing the disease; however, the presence of other genetic factors (called modifiers) as well as the person’s environment and lifestyle all influence whether or not the individual actually develops the disease1,5
  • Complex diseases represent an urgent unmet medical need but present a major challenge for researchers due to the multifactorial complexity of these disorders2,6

Examples of Complex Diseases

The vast majority of human diseases are classified as complex diseases. Examples include7–13:

  • Bowel
  • Breast
  • Ovarian
  • Melanoma
  • Prostate
  • Non-Hodgkin lymphoma

  • Asthma
  • Allergies
  • Emphysema

  • Diabetes

  • Cleft palate/lip
  • Neural tube defects such as spina bifida

  • Coronary heart disease
  • Rheumatic heart disease
  • Congenital heart disease
  • Stroke
  • Aortic aneurysm and dissection
  • Peripheral artery disease
  • Deep vein thrombosis and pulmonary embolism

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Multiple sclerosis
  • Type 1 diabetes mellitus
  • Psoriasis
  • Sjögren's syndrome
  • Inflammatory bowel disease (Crohn's disease, ulcerative colitis)

  • Arthritis
  • Rheumatic disorders
  • Osteoporosis

  • Alzheimer's disease
  • Schizophrenia
  • Bipolar disorder

  • Psoriasis
  • Eczema

Factors Contributing to Complex Diseases

Complex diseases arise from numerous genetic, environmental, and lifestyle factors14

Genetic Factors

  • Almost all complex diseases involve alterations in multiple genes that interact with one another14
  • Inheriting one or several disease-associated genes may predispose an individual to developing the disease phenotype1,14
  • Genetic factors include copy number variation, epistatic interactions, and modifier effects15

Environmental and Lifestyle Factors

  • Development of the disease is influenced by the environment and lifestyle of a genetically susceptible individual1,14
  • Environmental factors include exposure to allergens, carcinogens, or infectious agents14
  • Lifestyle factors include high-fat diet, lack of exercise, and smoking14

Treatment Strategies for Complex Diseases

Treating complex diseases is challenging due to the limited understanding of the specific factors that underlie these diseases3

  • Addressing one particular genetic abnormality is usually insufficient due to the presence of several genetic alterations that influence disease14,16,17
  • Current therapies for complex diseases can potentially convert fatal diseases into manageable conditions; however, available treatments for some complex diseases provide symptomatic relief while failing to reverse disease progression16,17
  • Targeted therapies have shown improved clinical outcomes, with many being approved in cancer treatment18,19
  • Gene therapy is under investigation as a treatment strategy for several complex diseases, particularly cancer, with some already approved for clinical use in cancer6,20–22

Complex diseases represent the majority of indications that are currently being addressed by gene therapy clinical trials20*

*Data as of 2017. Figure adapted from Ginn SL, et al. 201820.


  1. Craig J. Complex diseases: Research and applications. Nature Education. Available at: https://www.nature.com/scitable/topicpage/complex-diseases-research-and-applications-748/. Accessed June 16, 2020.
  2. He B, et al. J Cell Mol Med 2016;20(12):2231–2240.
  3. National Institutes of Health. What are complex or multifactorial disorders? Available at: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/complexdisorders. Accessed June 16, 2020.
  4. Wray J, et al. Cardiol Young 2014;24(2):220–228.
  5. National Institutes of Health. What does it mean to have a genetic predisposition to a disease? Available at: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/predisposition. Accessed July 7, 2020.
  6. Wang D, Gao G. Discov Med 2014;18(98):151–161.
  7. Cho JH, Gregersen PK. N Engl J Med 2011;365(17):1612–1623.
  8. Center for Genetics Education. Environmental and genetic interactions. Available at: http://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-11-environmental-and-genetic-interactions. Accessed June 16, 2020.
  9. Vieira A. Genes and diseases. Nature Education. Available at: https://www.nature.com/scitable/topic/genes-and-disease-17. Accessed June 16, 2020.
  10. Cavanaugh J, Consortium IBDIG. Am J Hum Genet 2001;68(5):1165–1171.
  11. National Institutes of Health. Sjögren syndrome. Available at: https://ghr.nlm.nih.gov/condition/sjogren-syndrome#genes. Accessed September 2, 2020.
  12. World Health Organization. Types of cardiovascular disease. Available at: https://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1. Accessed August 28, 2020.
  13. Zhang J, et al. Front Oncol 2018;8:657.
  14. National Human Genome Research Institute. Genetic analysis tools help define nature and nurture in complex disorders. Available at: https://www.genome.gov/10000865/complex-disorders-background/. Accessed June 16, 2020.
  15. Lobo I. Multifactorial inheritance and genetic diseases. Nature Education. Available at: https://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919/. Accessed June 16, 2020.
  16. Hughes R, et al. Front Neurosci 2016;10:177.
  17. Lyengar R. EMBO Rep 2013;14(12):1039–1042.
  18. National Cancer Institute. Targeted cancer therapies. Available at: https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet. Accessed June 15, 2020.
  19. Mahmoodi Chalbatani G, et al. Int J Nanomedicine 2019;14:3111–3128.
  20. Ginn SL, et al. J Gene Med 2018;20(5):e3015.
  21. Imlygic® [package insert]. 2019. Available at: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/imlygic/imlygic_pi.pdf. Accessed September 4, 2020.
  22. Tecartus [package insert]. 2020. Available at: https://www.fda.gov/media/140409/download. Accessed September 4, 2020.