The “Black Swan Principle” and the Genetics of Complex Diseases

From Top Italian Scientists Journal
January 13, 2024
The “Black Swan Principle” and the Genetics of Complex Diseases
Giuseppe Novelli, Juergen K V Reichardt
Black Swan Principle; Genetics of Complex Diseases
Download PDF
Download PDF

Giuseppe Novelli(a), Juergen K V Reichardt(b)

(a)Department of Biomedicine and Prevention, School of Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133, Rome, Italy and Department of Pharmacology, School of Medicine, University of Nevada, 89557, Reno, NV, USA.

(b)Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, QLD, 4878, Australia.

Correspondence to:


The black swan principle is a philosophy theory created by Nassim Nicholas Taleb that seeks to explain rare and unpredictable events, appearances that seem to defy logic or rational explanation. These events, termed "Black Swans," have been observed in various domains, including finance, public administration, infectious diseases, and ecology. The concept of Black Swans has gained recently, significant attention in academia and practice due to its relevance in understanding extreme and rare occurrences. The “black swan” concept has been used in genetics for the unexpected developments that genome sequencing would reveal and which could have consequences for healthcare systems (e.g., increase in often unnecessary and inappropriate diagnostic investigations, increase in non-patients, etc.).



The studies of G.N. on complex diseases are supported by grants of HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE) and HEAL ITALIA Health Extended ALliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine, PNRR MUR, Mission 4 Component 2.

Conflict of Interest

The Authors declare that there is no conflict of interest.


  1. Hannabuss S. The Black Swan: The Impact of the Highly Improbable. Library Review. 2008.
  2. Ponkin IV. ”Black Swan” Event as Manifestation of Uncertainties in Public Administration. Mediterranean Journal of Social Sciences. 2019.
  3. Velappan N, Davis-Anderson K, Deshpande A. Warning Signs of Potential Black Swan Outbreaks in Infectious Disease. Frontiers in Microbiology. 2022.
  4. Wind TR, Rijkeboer MM, Andersson G, Riper H. The COVID-19 Pandemic: The ‘Black Swan’ for Mental Health Care and a Turning Point for E-Health. Internet Interventions. 2020.
  5. Parameswar N, Chaubey A, Dhir S. Black Swan: Bibliometric Analysis and Development of Research Agenda. Benchmarking an International Journal. 2021.
  6. Simianer H, Reimer C. COVID-19: a "black swan" and what animal breeding can learn from it. Anim Front. 2021;11(1):57-9.
  7. Vacante M, D’Agata V, Motta M, Malaguarnera G, Biondi A, Basile F, et al. Centenarians and supercentenarians: a black swan. Emerging social, medical and surgical problems. BMC Surgery. 2012;12(1):S36.
  8. Doyle S. Waiting for medicine's black swans. CMAJ. 2012;184(5):E246-7.
  9. Jonsen AR, Durfy SJ, Burke W, Motulsky AG. The advent of the "unpatients'. Nat Med. 1996;2(6):622-4.
  10. Kish LJ, Topol EJ. Unpatients-why patients should own their medical data. Nat Biotechnol. 2015;33(9):921-4.
  11. Novelli G, Biancolella M, Latini A, Spallone A, Borgiani P, Papaluca M. Precision Medicine in Non-Communicable Diseases. High Throughput. 2020;9(1).
  12. Novelli G, Cassadonte C, Sbraccia P, Biancolella M. Genetics: A Starting Point for the Prevention and the Treatment of Obesity. Nutrients. 2023;15(12).
  13. Blanco-Gómez A, Castillo-Lluva S, Sáez-Freire MdM, Hontecillas-Prieto L, Mao JH, Castellanos A, et al. Missing Heritability of Complex Diseases: Enlightenment by Genetic Variants From Intermediate Phenotypes. Bioessays. 2016.
  14. Kim YH, Kim SI, Park B, Lee ES. Clinical Characteristics of Psoriasis for Initiation of Biologic Therapy: A Cluster Analysis. Annals of Dermatology. 2023.
  15. Levitan M. Textbook of human genetics. 3rd. ed. Oxford U.P1988.
  16. Lambert SA, Abraham G, Inouye M. Towards clinical utility of polygenic risk scores. Hum Mol Genet. 2019;28(R2):R133-r42.
  17. Blumberg RS, Dittel BN, Hafler DA, Herrath Mv, Nestle FO. Unraveling the Autoimmune Translational Research Process Layer by Layer. Nature Medicine. 2012.
  18. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the Missing Heritability of Complex Diseases. Nature. 2009.
  19. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-Wide Association Study Identifies New Susceptibility Loci for Crohn Disease and Implicates Autophagy in Disease Pathogenesis. Nature Genetics. 2007.
  20. Hou L, Bergen SE, Akula N, Song J, Hultman CM, Landén M, et al. Genome-Wide Association Study of 40,000 Individuals Identifies Two Novel Loci Associated With Bipolar Disorder. 2016.
  21. Ratnapriya R. Transcriptomics Insights Into Interpreting AMD-GWAS Discoveries for Biological and Clinical Applications. Journal of Translational Genetics and Genomics. 2022.
  22. Hindorff LA, Sethupathy P, Junkins H, Ramos EM, Mehta JP, Collins FS, et al. Potential Etiologic and Functional Implications of Genome-Wide Association Loci for Human Diseases and Traits. Proceedings of the National Academy of Sciences. 2009.
  23. Colona VL, Biancolella M, Novelli A, Novelli G. Will GWAS eventually allow the identification of genomic biomarkers for COVID-19 severity and mortality? J Clin Invest. 2021;131(23).
  24. Fatumo S, Sathan D, Samtal C, Isewon I, Tamuhla T, Soremekun C, et al. Polygenic risk scores for disease risk prediction in Africa: current challenges and future directions. Genome Med. 2023;15(1):87.
  25. Ginsburg GS, Denny JC, Schully SD. Data-driven science and diversity in the All of Us Research Program. Sci Transl Med. 2023;15(726):eade9214.
  26. Gouveia MH, Bentley AR, Leal TP, Tarazona-Santos E, Bustamante CD, Adeyemo AA, et al. Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies. Nat Commun. 2023;14(1):6802.
  27. Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk of complex disease. Curr Opin Genet Dev. 2008;18(3):257-63.
  28. Gibson G. Rare and common variants: twenty arguments. Nat Rev Genet. 2012;13(2):135-45.
  29. Falconer DS. Introduction to quantitative genetics: Pearson Education India; 1996.
  30. Taleb N. The black swan : the impact of the highly improbable. Penguin Books ed. London: Penguin; 2008. xxviii, 366 p. p.
  31. Casanova JL, Abel L. From rare disorders of immunity to common determinants of infection: Following the mechanistic thread. Cell. 2022;185(17):3086-103.
  32. Cobat A, Zhang Q, Abel L, Casanova JL, Fellay J. Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants. Annu Rev Biomed Data Sci. 2023;6:465-86.
  33. Fei C-J, Li Z-Y, Ning J, Yang L, Wu B-S, Kang J-J, et al. Exome sequencing identifies genes associated with sleep-related traits. Nature Human Behaviour. 2024.
  34. Bomba L, Walter K, Soranzo N. The impact of rare and low-frequency genetic variants in common disease. Genome Biology. 2017;18(1):77.
  35. Pounraja VK, Girirajan S. A general framework for identifying oligogenic combinations of rare variants in complex disorders. Genome Res. 2022;32(5):904-15.
  36. Fu W, O'Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2013;493(7431):216-20.
  37. Momozawa Y, Mizukami K. Unique roles of rare variants in the genetics of complex diseases in humans. J Hum Genet. 2021;66(1):11-23.
  38. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.
  39. Notarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020;5(49).
  40. Matuozzo D, Talouarn E, Marchal A, Zhang P, Manry J, Seeleuthner Y, et al. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19. Genome Med. 2023;15(1):22.
  41. Biancolella M, Colona VL, Luzzatto L, Watt JL, Mattiuz G, Conticello SG, et al. COVID-19 annual update: a narrative review. Hum Genomics. 2023;17(1):68.
  42. Lee D, Le Pen J, Yatim A, Dong B, Aquino Y, Ogishi M, et al. Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children. Science. 2023;379(6632):eabo3627.
  43. Lali R, Chong M, Omidi A, Mohammadi-Shemirani P, Le A, Cui E, et al. Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories. Nature Communications. 2021;12(1):5852.
  44. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72.
  45. Hernandez RD, Uricchio LH, Hartman K, Ye C, Dahl A, Zaitlen N. Ultrarare variants drive substantial cis heritability of human gene expression. Nat Genet. 2019;51(9):1349-55.
  46. Wakeling MN, Owens NDL, Hopkinson JR, Johnson MB, Houghton JAL, Dastamani A, et al. Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism. Nat Genet. 2022;54(11):1615-20.
  47. Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, et al. ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(8):100866.
  48. Jensson BO, Arnadottir GA, Katrinardottir H, Fridriksdottir R, Helgason H, Oddsson A, et al. Actionable Genotypes and Their Association with Life Span in Iceland. New England Journal of Medicine. 2023;389(19):1741-52.