Journal of Assisted Reproduction and Genetics

, Volume 32, Issue 4, pp 495–508 | Cite as

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction

  • Merlin G. Butler
  • Austen McGuire
  • Ann M. Manzardo



Obesity is a growing public health concern now reaching epidemic status worldwide for children and adults due to multiple problems impacting on energy intake and expenditure with influences on human reproduction and infertility. A positive family history and genetic factors are known to play a role in obesity by influencing eating behavior, weight and level of physical activity and also contributing to human reproduction and infertility. Recent advances in genetic technology have led to discoveries of new susceptibility genes for obesity and causation of infertility. The goal of our study was to provide an update of clinically relevant candidate and known genes for obesity and infertility using high resolution chromosome ideograms with gene symbols and tabular form.


We used computer-based internet websites including PubMed to search for combinations of key words such as obesity, body mass index, infertility, reproduction, azoospermia, endometriosis, diminished ovarian reserve, estrogen along with genetics, gene mutations or variants to identify evidence for development of a master list of recognized obesity genes in humans and those involved with infertility and reproduction. Gene symbols for known and candidate genes for obesity were plotted on high resolution chromosome ideograms at the 850 band level. Both infertility and obesity genes were listed separately in alphabetical order in tabular form and those highlighted when involved with both conditions.


By searching the medical literature and computer generated websites for key words, we found documented evidence for 370 genes playing a role in obesity and 153 genes for human reproduction or infertility. The obesity genes primarily affected common pathways in lipid metabolism, deposition or transport, eating behavior and food selection, physical activity or energy expenditure. Twenty-one of the obesity genes were also associated with human infertility and reproduction. Gene symbols were plotted on high resolution ideograms and their name, precise chromosome band location and description were summarized in tabular form.


Meaningful correlations in the obesity phenotype and associated human infertility and reproduction are represented with the location of genes on chromosome ideograms along with description of the gene and position in tabular form. These high resolution chromosome ideograms and tables will be useful in genetic awareness and counseling, diagnosis and treatment to improve clinical outcomes.


Obesity Obesity susceptibility genes Gene symbols Human infertility and reproduction High resolution chromosome ideogram 



We thank Carla Meister for expert preparation of the manuscript, Dr. Syed Rafi for assistance in literature review and Lorie Gavulic for excellent artistic design and preparation of chromosome ideograms.


Partial funding support was provided by the Prader-Willi Syndrome Association (USA), the Headley Family Scholarship, the National Institute of Child Health and Human Development (NICHD) HD02528 and from the Angelman, Rett and Prader-Willi Syndromes Consortium (U54 HD06122) which is part of the National Institute of Health (NIH) Rare Disease Clinical Research Network (RDCRN) supported through collaboration between the NIH Office of Rare Disease Research (ORDR) at the National Center of Advancing Translational Science (NCATS) and NICHD. The content is solely the responsibility of the authors and does not necessarily represent the office views of the National Institutes of Health.

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond). 2008;32:1431–7.CrossRefGoogle Scholar
  2. 2.
    de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr. 2010;92:1257–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Marsh CA, Hecker E. Maternal obesity and adverse reproductive outcomes: reducing the risk. Obstet Gynecol Surv. 2014;69:622–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006;295:1549–55.CrossRefPubMedGoogle Scholar
  5. 5.
    Pandey S, Pandey S, Maheshwari A, Bhattacharya S. The impact of female obesity on the outcome of fertility treatment. J Hum Reprod Sci. 2010;3:62–7.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Silber SJ, Barbey N. Scientific molecular basis for treatment of reproductive failure in the human: an insight into the future. Biochim Biophys Acta. 1822;2012:1981–96.Google Scholar
  7. 7.
    Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007;298:2028–37.CrossRefPubMedGoogle Scholar
  8. 8.
    Jungheim ES, Travieso JL, Carson KR, Moley KH. Obesity and reproductive function. Obstet Gynecol Clin North Am. 2012;39:479–93.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Kort JD, Winget C, Kim SH, Lathi RB. A retrospective cohort study to evaluate the impact of meaningful weight loss on fertility outcomes in an overweight population with infertility. Fertil Steril. 2014;101:1400–3.CrossRefPubMedGoogle Scholar
  10. 10.
    Guelinckx I, Devlieger R, Vansant G. Reproductive outcome after bariatric surgery: a critical review. Hum Reprod Update. 2009;15:189–201.CrossRefPubMedGoogle Scholar
  11. 11.
    Peng CY, Xie HJ, Guo ZF, Nie YL, Chen J, Zhou JM, et al. The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: a case–control study and meta-analysis. J Assist Reprod Genet. 2014;31:1211–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Reilly JJ, Armstrong J, Dorosty AR, Emmett PM, Ness A, Rogers I, et al. Early life risk factors for obesity in childhood: cohort study. BMJ. 2005;330:1357.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Hjelmborg J, Fagnani C, Silventoinen K, McGue M, Korkeila M, Christensen K, et al. Genetic influences on growth traits of BMI: a longitudinal study of adult twins. Obesity (Silver Spring). 2008;16:847–52.CrossRefGoogle Scholar
  14. 14.
    Carnell S, Haworth CM, Plomin R, Wardle J. Genetic influence on appetite in children. Int J Obes (Lond). 2008;32:1468–73.CrossRefGoogle Scholar
  15. 15.
    Mustelin L, Latvala A, Pietilainen KH, Piirila P, Sovijarvi AR, Kujala UM, et al. Associations between sports participation, cardiorespiratory fitness, and adiposity in young adult twins. J Appl Physiol. 2011;110:681–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Bouchard C, Tremblay A, Nadeau A, Despres JP, Theriault G, Boulay MR, et al. Genetic effect in resting and exercise metabolic rates. Metabolism. 1989;38:364–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Cheung WW, Mao P. Recent advances in obesity: genetics and beyond. ISRN Endocrinol. 2012; 536905.Google Scholar
  18. 18.
    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443:289–95.CrossRefPubMedGoogle Scholar
  19. 19.
    Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2010;463:666–70.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Choquet H, Meyre D. Genetics of obesity: what have we learned? Curr Genomics. 2011;12:169–79.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Choquet H, Meyre D. Molecular basis of obesity: current status and future prospects. Curr Genomics. 2011;12:154–68.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–47.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Govaerts C, Srinivasan S, Shapiro A, Zhang S, Picard F, Clement K, et al. Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function. Peptides. 2005;26:1909–19.CrossRefPubMedGoogle Scholar
  24. 24.
    Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring). 2006;14:529–644.CrossRefGoogle Scholar
  25. 25.
    Butler MG. Prader-Willi syndrome: obesity due to genomic imprinting. Curr Genomics. 2011;12(3):204–15.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Herrera BM, Keildson S, Lindgren CM. Genetics and epigenetics of obesity. Maturitas. 2011;69:41–9.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition. 2004;20:63–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nat Rev Genet. 2006;7:85–97.CrossRefPubMedGoogle Scholar
  29. 29.
    Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med. 2010;12:641–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Dasouki MJ, Youngs EL, Hovanes K. Structural chromosome abnormalities associated with obesity: report of four new subjects and review of literature. Curr Genomics. 2011;12:190–203.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40:768–75.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Layman LC. Human gene mutations causing infertility. J Med Genet. 2002;39:153–61.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Okada Y, Tateishi K, Zhang Y. Histone demethylase JHDM2A is involved in male infertility and obesity. J Androl. 2010;31:75–8.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Kosova G, Scott NM, Niederberger C, Prins GS, Ober C. Genome-wide association study identifies candidate genes for male fertility traits in humans. Am J Hum Genet. 2012;90:950–61.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    El Inati E, Muller J, Viville S. Autosomal mutations and human spermatogenic failure. Biochim Biophys Acta. 1822;2012:1873–9.Google Scholar
  36. 36.
    Qiu R, Chen C, Jiang H, Shen L, Wu M, Liu C. Large genomic region free of GWAS-based common variants contains fertility-related genes. PLoS One. 2013;8:e61917.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Ferfouri F, Boitrelle F, Ghout I, Albert M, Molina Gomes D, Wainer R, et al. A genome-wide DNA methylation study in azoospermia. Andrology. 2013;1:815–21.CrossRefPubMedGoogle Scholar
  38. 38.
    Albertsen HM, Chettier R, Farrington P, Ward K. Genome-wide association study link novel loci to endometriosis. PLoS One. 2013;8:e58257.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Fragouli E, Lalioti MD, Wells D. The transcriptome of follicular cells: biological insights and clinical implications for the treatment of infertility. Hum Reprod Update. 2014;20:1–11.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Bulun SE. Aromatase and estrogen receptor alpha deficiency. Fertil Steril. 2014;101:323–9.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Greene AD, Patounakis G, Segars JH. Genetic associations with diminished ovarian reserve: a systematic review of the literature. J Assist Reprod Genet. 2014;31:935–46.CrossRefPubMedGoogle Scholar
  42. 42.
    Qin Y, Ji J, Du G, Wu W, Dai J, Hu Z, et al. Comprehensive pathway-based analysis identifies associations of BCL2, GNAO1 and CHD2 with non-obstructive azoospermia risk. Hum Reprod. 2014;29:860–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum Reprod Update. 2014;20:702–16.CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Hu Z, Li Z, Yu J, Tong C, Lin Y, Guo X, et al. Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men. Nat Commun. 2014;5:3857.PubMedGoogle Scholar
  45. 45.
    D’Angelo CS, Da Paz JA, Kim CA, Bertola DR, Castro CI, Varela MC, et al. Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems. Eur J Med Genet. 2006;49:451–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Faivre L, Cormier-Daire V, Lapierre JM, Colleaux L, Jacquemont S, Genevieve D, et al. Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. J Med Genet. 2002;39:594–6.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Gul D, Ogur G, Tunca Y, Ozcan O. Third case of WAGR syndrome with severe obesity and constitutional deletion of chromosome (11)(p12p14). Am J Med Genet. 2002;107:70–1.CrossRefPubMedGoogle Scholar
  48. 48.
    van den Berg L, de Waal HD, Han JC, Ylstra B, Eijk P, Nesterova M, et al. Investigation of a patient with a partial trisomy 16q including the fat mass and obesity associated gene (FTO): fine mapping and FTO gene expression study. Am J Med Genet A. 2010;152A:630–7.CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Cody JD, Reveles XT, Hale DE, Lehman D, Coon H, Leach RJ. Haplosufficiency of the melancortin-4 receptor gene in individuals with deletions of 18q. Hum Genet. 1999;105:424–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Aldred MA, Aftimos S, Hall C, Waters KS, Thakker RV, Trembath RC, et al. Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy. Am J Med Genet. 2002;113:167–72.CrossRefPubMedGoogle Scholar
  51. 51.
    D’Angelo CS, Jehee FS, Koiffmann CP. An inherited atypical 1 Mb 22q11.2 deletion within the DGS/VCFS 3 Mb region in a child with obesity and aggressive behavior. Am J Med Genet A. 2007;143A:1928–32.Google Scholar
  52. 52.
    Hirst M, Grewal P, Flannery A, Slatter R, Maher E, Barton D, et al. Two new cases of FMR1 deletion associated with mental impairment. Am J Hum Genet. 1995;56:67–74.CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, et al. A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes. 2004;53:803–11.CrossRefPubMedGoogle Scholar
  54. 54.
    Stone S, Abkevich V, Hunt SC, Gutin A, Russell DL, Neff CD, et al. A major predisposition locus for severe obesity, at 4p15-p14. Am J Hum Genet. 2002;70:1459–68.CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2009;41:25–34.CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet. 2009;41:18–24.CrossRefPubMedGoogle Scholar
  57. 57.
    Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42:937–48.CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L, et al. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet. 2009;5:e1000508.CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P, et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet. 2008;40:716–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S, et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet. 2009;41:157–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Scherag A, Dina C, Hinney A, et al. Two new loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups. PLoS Genet. 2010;6:e1000916.CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Montgomery GW, Zondervan KT, Nyholt DR. The future for genetic studies in reproduction. Mole Hum Reprod. 2014;20(1):1–14.CrossRefGoogle Scholar
  63. 63.
    Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to pregnancy. Hum Reprod. 2007;22:414–20.CrossRefPubMedGoogle Scholar
  64. 64.
    Wise LA, Rothman KJ, Mikkelsen EM, Sorensen HT, Riis A, Hatch EE. An internet-based prospective study of body size and time-to-pregnancy. Hum Reprod. 2010;25:253–64.CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Rich-Edwards JW, Goldman MB, Willett WC, Hunter DJ, Stampfer MJ, Colditz GA, et al. Adolescent body mass index and infertility caused by ovulatory disorder. Am J Obstet Gynecol. 1994;171:171–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Metwally M, Li TC, Ledger WL. The impact of obesity on female reproductive function. Obes Rev. 2007;8:515–23.CrossRefPubMedGoogle Scholar
  67. 67.
    Gil-Campos M, Canete RR, Gil A. Adiponectin, the missing link in insulin resistance and obesity. Clin Nutr. 2004;23:963–74.CrossRefPubMedGoogle Scholar
  68. 68.
    Brannian JD, Hansen KA. Leptin and ovarian folliculogenesis: implications for ovulation induction and ART outcomes. Semin Reprod Med. 2002;20:103–12.CrossRefPubMedGoogle Scholar
  69. 69.
    Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil Steril. 2002;77:433–44.CrossRefPubMedGoogle Scholar
  70. 70.
    Bergh C, Carlsson B, Olsson JH, Selleskog U, Hillensjo T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil Steril. 1993;59:323–31.PubMedGoogle Scholar
  71. 71.
    Balen AH, Platteau P, Andersen AN, Devroey P, Sorensen P, Helmgaard L, et al. The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility. BJOG. 2006;113:1195–202.CrossRefPubMedGoogle Scholar
  72. 72.
    Zaadstra BM, Seidell JC, Van Noord PA, te Velde ER, Habbema JD, Vrieswijk B, et al. Fat and female fecundity: prospective study of effect of body fat distribution on conception rates. BMJ. 1993;306:484–7.CrossRefPubMedCentralPubMedGoogle Scholar
  73. 73.
    Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology–a systematic review. Hum Reprod Update. 2007;13:433–44.CrossRefPubMedGoogle Scholar
  74. 74.
    Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age. Ann N Y Acad Sci. 2006;1092:158–74.CrossRefPubMedGoogle Scholar
  75. 75.
    Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223–36.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Merlin G. Butler
    • 1
  • Austen McGuire
    • 1
  • Ann M. Manzardo
    • 1
  1. 1.Departments of Psychiatry & Behavioral Sciences and PediatricsUniversity of Kansas Medical CenterKansas CityUSA

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