A Review of Genome Wide Association Studies for Erectile Dysfunction

  • Darshan P. Patel
  • Alexander W. Pastuszak
  • James M. HotalingEmail author
Female Sexual Dysfunction and Disorders (A Pastuszak and N Thirumavalavan, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Female Sexual Dysfunction and Disorders


Purpose of Review

To review large cohort genome wide association studies for erectile dysfunction.

Recent Findings

Two recent genome wide association studies using the Genetic Epidemiology Research in Adult Health and Aging cohort, UK Biobank, and the Partners HealthCare Biobank have identified an association between unique single nucleotide polymorphisms involved in the regulatory activity of single-minded homolog 1 (SIM1) and risk of erectile dysfunction. SIM1 is involved in the leptin-melanocortin pathway and may contribute to centrally mediated erectile dysfunction.


Identification of novel loci associated with erectile function from genome wide association studies will help expand the understanding of the breadth of pathways that contribute to erectile dysfunction. This will help accelerate studies of novel therapies for the treatment of erectile dysfunction.


Erectile dysfunction Sexual dysfunction, physiological Genome-wide association study Genetic therapy SIM1 protein, human 


Compliance with Ethical Standards

Conflict of Interest

Dr. Patel has nothing to disclosure regarding the material discussed in this article.

Dr. Pastuszak reports his associations with Endo Pharmaceuticals – advisor, speaker, consultant, research and fellowship support; Antares Pharmaceuticals – advisor; and Woven Health – founder and leadership position.

Dr. Hotaling reports associations with Endo Pharmaceuticals – research and fellowship grant; Boston Scientific – fellowship grant; Nanonc, StreamDx, Andro360 – leadership position/founder.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Intern Med. 2003;139(3):161–8.CrossRefGoogle Scholar
  2. 2.
    Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281(6):537–44.CrossRefGoogle Scholar
  3. 3.
    McCabe MP, Sharlip ID, Lewis R, Atalla E, Balon R, Fisher AD, et al. Risk factors for sexual dysfunction among women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. J Sex Med. 2016;13(2):153–67.CrossRefGoogle Scholar
  4. 4.
    Fischer ME, Vitek ME, Hedeker D, Henderson WG, Jacobsen SJ, Goldberg J. A twin study of erectile dysfunction. Arch Intern Med. 2004;164(2):165–8.CrossRefGoogle Scholar
  5. 5.
    Lopushnyan NA, Chitaley K. Genetics of erectile dysfunction. J Urol. 2012;188(5):1676–83.CrossRefGoogle Scholar
  6. 6.
    •• Yao HX, Ma FZ, Tan YY, Liu LY. Endothelial nitric oxide synthase gene polymorphisms and risk of erectile dysfunction: an updated meta-analysis of genetic association studies. Int J Surg. 2018;54(Pt A):141–8. This is a comprehensive meta-analysis of endothelial nitric oxide synthase gene polymorphisms and risk of erectile dysfunction.CrossRefGoogle Scholar
  7. 7.
    Zhang T, Li WL, He XF, Wu ZY, Liu LH, He SH, et al. The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene and erectile dysfunction risk: a meta-analysis. Andrology. 2013;1(2):274–80.CrossRefGoogle Scholar
  8. 8.
    Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, et al. 10 Years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101(1):5–22.CrossRefGoogle Scholar
  9. 9.
    Tam V, Patel N, Turcotte M, Bosse Y, Pare G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019. Scholar
  10. 10.
    Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47(D1):D1005–d12.CrossRefGoogle Scholar
  11. 11.
    Evans DM, Brion MJ, Paternoster L, Kemp JP, McMahon G, Munafo M, et al. Mining the human phenome using allelic scores that index biological intermediates. PLoS Genet. 2013;9(10):e1003919.CrossRefGoogle Scholar
  12. 12.
    Evans DM, Visscher PM, Wray NR. Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum Mol Genet. 2009;18(18):3525–31.CrossRefGoogle Scholar
  13. 13.
    Slatkin M. Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. Nat Rev Genet. 2008;9(6):477–85.CrossRefGoogle Scholar
  14. 14.
    Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008;322(5903):881–8.CrossRefGoogle Scholar
  15. 15.
    Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014;46(4):357–63.CrossRefGoogle Scholar
  16. 16.
    Wessells H, Joyce GF, Wise M, Wilt TJ. Erectile dysfunction. J Urol. 2007;177(5):1675–81.CrossRefGoogle Scholar
  17. 17.
    Nelson MR, Tipney H, Painter JL, Shen J, Nicoletti P, Shen Y, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47(8):856–60.CrossRefGoogle Scholar
  18. 18.
    Hotaling JM, Waggott DR, Goldberg J, Jarvik G, Paterson AD, Cleary PA, et al. Pilot genome-wide association search identifies potential loci for risk of erectile dysfunction in type 1 diabetes using the DCCT/EDIC study cohort. J Urol. 2012;188(2):514–20.CrossRefGoogle Scholar
  19. 19.
    •• Jorgenson E, Matharu N, Palmer MR, Yin J, Shan J, Hoffmann TJ, et al. Genetic variation in the SIM1 locus is associated with erectile dysfunction. Proc Natl Acad Sci USA. 2018;115(43):11018–23. Recent large genome wide association study that identified a single locus near theSIM1gene, involved in the leptin-melanocortin pathway, that was associated with risk of erectile dysfunction independent of known risk factors.CrossRefGoogle Scholar
  20. 20.
    Wikberg JE, Mutulis F. Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov. 2008;7(4):307–23.CrossRefGoogle Scholar
  21. 21.
    Wessells H, Levine N, Hadley ME, Dorr R, Hruby V. Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II. Int J Impot Res. 2000;12(Suppl 4):S74–9.CrossRefGoogle Scholar
  22. 22.
    Semple E, Hill JW. Sim1 neurons are sufficient for MC4R-mediated sexual function in male mice. Endocrinology. 2018;159(1):439–49.CrossRefGoogle Scholar
  23. 23.
    •• Bovijn J, Jackson L, Censin J, Chen CY, Laisk T, Laber S, et al. GWAS identifies risk locus for erectile dysfunction and implicates hypothalamic neurobiology and diabetes in etiology. Am J Hum Genet. 2019;104(1):157–63. Recent large genome wide association study identifying additional locus near theSIM1gene associated with erectile dysfunction risk.Google Scholar
  24. 24.
    Maeder ML, Gersbach CA. Genome-editing technologies for gene and cell therapy. Mol Ther. 2016;24(3):430–46.CrossRefGoogle Scholar
  25. 25.
    Patel DP, Pastuszak AW, Hotaling JM. Emerging treatments for erectile dysfunction: a review of novel, non-surgical options. Curr Urol Rep. 2019;20(8):44.CrossRefGoogle Scholar
  26. 26.
    Yu B, Wu C, Li T, Qin F, Yuan J. Advances in gene therapy for erectile dysfunction: promises and challenges. Curr Gene Ther. 2018;18(6):351–65.CrossRefGoogle Scholar
  27. 27.
    Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum Gene Ther. 2006;17(12):1165–76.CrossRefGoogle Scholar
  28. 28.
    Reed-Maldonado AB, Lue TF. The current status of stem-cell therapy in erectile dysfunction: a review. World J Mens Health. 2016;34(3):155–64.CrossRefGoogle Scholar
  29. 29.
    Soebadi MA, Moris L, Castiglione F, Weyne E, Albersen M. Advances in stem cell research for the treatment of male sexual dysfunctions. Curr Opin Urol. 2016;26(2):129–39.CrossRefGoogle Scholar
  30. 30.
    Bivalacqua TJ, Champion HC, Abdel-Mageed AB, Kadowitz PJ, Hellstrom WJ. Gene transfer of prepro-calcitonin gene-related peptide restores erectile function in the aged rat. Biol Reprod. 2001;65(5):1371–7.CrossRefGoogle Scholar
  31. 31.
    Lu J, Xin Z, Zhang Q, Cui D, Xiao Y, Zhuo J, et al. Beneficial effect of PEDF-transfected ADSCs on erectile dysfunction in a streptozotocin-diabetic rat model. Cell Tissue Res. 2016;366(3):623–37.CrossRefGoogle Scholar
  32. 32.
    Ryu JK, Cho CH, Shin HY, Song SU, Oh SM, Lee M, et al. Combined angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia. Mol Ther. 2006;13(4):705–15.CrossRefGoogle Scholar
  33. 33.
    Ahmadzadeh V, Farajnia S, Baghban R, Rahbarnia L, Zarredar H. CRISPR-Cas system: toward a more efficient technology for genome editing and beyond. J Cell Biochem. 2019. Scholar
  34. 34.
    • Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol. 2019. Informative review on the use of CRISPR-Cas technologies for gene editing.CrossRefGoogle Scholar
  35. 35.
    Burnett AL, Nehra A, Breau RH, Culkin DJ, Faraday MM, Hakim LS, et al. Erectile Dysfunction: AUA Guideline. J Urol. 2018;200(3):633–41.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Darshan P. Patel
    • 1
  • Alexander W. Pastuszak
    • 1
  • James M. Hotaling
    • 1
    Email author
  1. 1.Division of Urology, Department of SurgeryUniversity of Utah Health, University of Utah School of MedicineSalt Lake CityUSA

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