Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder

Subjects

Abstract

Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher’s exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Winokur G, Clayton PJ, Reich T . Manic Depressive Illness. C. V. Mosby, 1969.

    Google Scholar 

  2. Shopsin B . Manic Illness. Raven Press: New York, 1979.

    Google Scholar 

  3. Goodwin FK, Jamison KR . Manic-Depressive Illness. Oxford University Press: Oxford, 1991.

    Google Scholar 

  4. Pauls DL, Morton LA, Egeland JA . Risks of affective illness among first-degree relatives of bipolar I old-order Amish probands. Arch Gen Psychiatr 1992; 49: 703–708.

    Article  CAS  PubMed  Google Scholar 

  5. McKusick VA, Hostetler JA, Egeland JA, Eldridge R . The distribution of certain genes in the Old Order Amish. Cold Spring Harb Symp Quant Biol 1964; 29: 99–114.

    Article  CAS  PubMed  Google Scholar 

  6. Craddock N, Sklar P . Genetics of bipolar disorder. Lancet 2013; 381: 1654–1662.

    Article  CAS  PubMed  Google Scholar 

  7. Fagnani C, Bellani M, Soares JC, Stazi MA, Brambilla P . Discordant twins as a tool to unravel the aetiology of bipolar disorder. Epidemiol Psychiatr Sci 2014; 23: 137–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen DT, Jiang X, Akula N, Shugart YY, Wendland JR, Steele CJ et al. Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatr 2013; 18: 195–205.

    Article  CAS  Google Scholar 

  9. Georgi B, Craig D, Kember RL, Liu W, Lindquist I, Nasser S et al. Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate. PLoS Genet 2014; 10: e1004229.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gershon ES, Alliey-Rodriguez N, Liu C . After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. Am J Psychiatr 2011; 168: 253–256.

    Article  PubMed  Google Scholar 

  11. Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E et al. Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatr 2009; 14: 252–260.

    Article  CAS  Google Scholar 

  12. Nurnberger JI Jr, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I et al. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatr 2014; 71: 657–664.

    Article  CAS  Google Scholar 

  13. Serretti A, Mandelli L . The genetics of bipolar disorder: genome 'hot regions,' genes, new potential candidates and future directions. Molecular Psychiatr 2008; 13: 742–771.

    Article  CAS  Google Scholar 

  14. Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G et al. A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatr 2013; 18: 497–511.

    Article  CAS  Google Scholar 

  15. Wray NR, Lee SH, Kendler KS . Impact of diagnostic misclassification on estimation of genetic correlations using genome-wide genotypes. Eur J Hum Genet 2012; 20: 668–674.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ginns EI St, Jean P, Philibert RA, Galdzicka M, Damschroder-Williams P, Thiel B et al. A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish. Proc Nati Acad Sci USA 1998; 95: 15531–15536.

    Article  CAS  Google Scholar 

  17. Visscher PM, Haley CS, Ewald H, Mors O, Egeland J, Thiel B et al. Joint multi-population analysis for genetic linkage of bipolar disorder or ‘wellness’ to chromosome 4p. Am J Med Genet Part B, Neuropsychiatr Genet 2005; 133B: 18–24.

    Article  CAS  Google Scholar 

  18. Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 2000; 24: 283–286.

    Article  CAS  PubMed  Google Scholar 

  19. Galdzicka M, Egeland J, Ginns E . EVC and EVC2 and the Ellis-van Creveld Syndrome and Weyers Acrofacial Dysostosis, 2nd edn. Oxford University Press: New York, USA, 2008.

  20. McKusick VA, Egeland JA, Eldridge R, Krusen DE . Dwarfism in the Amish I. The Ellis-Van Creveld Syndrome. Bull Johns Hopkins Hosp 1964; 115: 306–336.

    CAS  PubMed  Google Scholar 

  21. Fisher JM . Descendants and history of Christian Fisher family. Private Publisher: Ronks, PA, USA, 1957; p. 619.

    Google Scholar 

  22. McKusick VA, Hostetler JA, Egeland JA . Genetic studies of the Amish, background and potentialities. Bull Johns Hopkins Hosp 1964; 115: 203–222.

    CAS  PubMed  Google Scholar 

  23. Egeland JA (ed). Descendants of Christian Fisher and other Amish-Mennonite Pioneer Families. Moore Clinic: Baltimore, MD, USA, 1972.

  24. Egeland JA, Hostetter AM . Amish Study, I: Affective disorders among the Amish, 1976-1980. Am J Psychiatr 1983; 140: 56–61.

    Article  CAS  PubMed  Google Scholar 

  25. Egeland JA, Sussex JN, Endicott J, Hostetter AM . The impact of diagnoses on genetic linkage study for bipolar affective disorders among the Amish. Psychiatr Genet 1990; 1: 5–18.

    Google Scholar 

  26. Hostetter AM, Egeland JA, Endicott J . Amish Study, II: Consensus diagnoses and reliability results. Am J Psychiatr 1983; 140: 62–66.

    Article  CAS  PubMed  Google Scholar 

  27. Spitzer RL, Endicott J, Robins E . Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatr 1978; 35: 773–782.

    Article  CAS  PubMed  Google Scholar 

  28. Association Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Publishing: Arlington, VA, 2000.

  29. Chakravarti A, Clark AG, Mootha VK . Distilling pathophysiology from complex disease genetics. Cell 2013; 155: 21–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chiesa G, Sirtori CR . Apolipoprotein A-I(Milano): current perspectives. Curr Opin Lipidol 2003; 14: 159–163.

    Article  CAS  PubMed  Google Scholar 

  31. Shevah O, Laron Z . Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Hormone IGF Res 2007; 17: 54–57.

    Article  CAS  Google Scholar 

  32. Steuerman R, Shevah O, Laron Z . Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol 2011; 164: 485–489.

    Article  CAS  PubMed  Google Scholar 

  33. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 2011; 3: 70ra13.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012; 488: 96–99.

    Article  CAS  PubMed  Google Scholar 

  35. Yang C, Chen W, Chen Y, Jiang J . Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell Res 2012; 22: 1593–1604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruiz-Perez VL, Goodship JA . Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands. Am J Med Genet Part C, 2009; 151C: 341–351.

    Article  CAS  Google Scholar 

  37. Pusapati GV, Hughes CE, Dorn KV, Zhang D, Sugianto P, Aravind L et al. EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia. Dev Cell 2014; 28: 483–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nakatomi M, Hovorakova M, Gritli-Linde A, Blair HJ, MacArthur K, Peterka M et al. Evc regulates a symmetrical response to Shh signaling in molar development. J Dental Res 2013; 92: 222–228.

    Article  CAS  Google Scholar 

  39. Green JA, Mykytyn K . Neuronal primary cilia: an underappreciated signaling and sensory organelle in the brain. Neuropsychopharmacology 2014; 39: 244–245.

    Article  CAS  PubMed  Google Scholar 

  40. Macdonald TJ . Hedgehog pathway in pediatric cancers: they're not just for brain tumors anymore. Am Soc Clin Oncol Soc 2012; 605–609.

  41. Ming JE, Roessler E, Muenke M . Human developmental disorders and the Sonic hedgehog pathway. Mol Med Today 1998; 4: 343–349.

    Article  CAS  PubMed  Google Scholar 

  42. Muenke M, Cohen MM Jr . Genetic approaches to understanding brain development: holoprosencephaly as a model. Mental Retard Dev Disabl Res Rev 2000; 6: 15–21.

    Article  CAS  Google Scholar 

  43. Oldak M, Grzela T, Lazarczyk M, Malejczyk J, Skopinski P . Clinical aspects of disrupted Hedgehog signaling (Review). Int J Mol Med 2001; 8: 445–452.

    CAS  PubMed  Google Scholar 

  44. Roessler E, Muenke M . Holoprosencephaly: a paradigm for the complex genetics of brain development. J Inherit Metab Dis 1998; 21: 481–497.

    Article  CAS  PubMed  Google Scholar 

  45. Vaillant C, Monard D . SHH pathway and cerebellar development. Cerebellum 2009; 8: 291–301.

    Article  PubMed  Google Scholar 

  46. Galdzicka M, Patnala S, Hirshman MG, Cai JF, Nitowsky H, Egeland JA et al. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab 2002; 77: 291–295.

    Article  CAS  PubMed  Google Scholar 

  47. Ruiz i Altaba A, Palma V, Dahmane N . Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 2002; 3: 24–33.

    Article  CAS  PubMed  Google Scholar 

  48. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993; 75: 1417–1430.

    Article  CAS  PubMed  Google Scholar 

  49. Panovska-Griffiths J, Page KM, Briscoe . A gene regulatory motif that generates oscillatory or multiway switch outputs. J Royal Soc 2013; 10: 20120826.

    Google Scholar 

  50. Balaskas N, Ribeiro A, Panovska J, Dessaud E, Sasai N, Page KM et al. Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube. Cell 2012; 148: 273–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kwon HJ . ATP oscillations mediate inductive action of FGF and Shh signalling on prechondrogenic condensation. Cell Biochem Funct 2013; 31: 75–81.

    Article  CAS  PubMed  Google Scholar 

  52. Traiffort E, Angot E, Ruat M . Sonic Hedgehog signaling in the mammalian brain. J Neurochem 2010; 113: 576–590.

    Article  CAS  PubMed  Google Scholar 

  53. Ruat M, Angot E, Traiffort E . Shh signal and its functional roles in normal and diseased brain. Med Sci 2011; 27: 979–985.

    Google Scholar 

  54. Gradilla AC, Guerrero I . Hedgehog on the move: a precise spatial control of Hedgehog dispersion shapes the gradient. Curr Opin Genet Devel 2013; 23: 363–373.

    Article  CAS  Google Scholar 

  55. Odenthal J, Haffter P, Vogelsang E, Brand M, van Eeden FJ, Furutani-Seiki M et al. Mutations affecting the formation of the notochord in the zebrafish, Danio rerio. Development 1996; 123: 103–115.

    CAS  PubMed  Google Scholar 

  56. Bejsovec A, Wieschaus E . Segment polarity gene interactions modulate epidermal patterning in Drosophila embryos. Development 1993; 119: 501–517.

    CAS  PubMed  Google Scholar 

  57. Oyabu A, Narita M, Tashiro Y . The effects of prenatal exposure to valproic acid on the initial development of serotonergic neurons. Int J Devel Neurosci 2013; 31: 202–208.

    Article  CAS  Google Scholar 

  58. Can A, Schulze TG, Gould TD . Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacol Biochem Behav 2014; 123C: 3–16.

    Article  Google Scholar 

  59. Banerjee SB, Rajendran R, Dias BG, Ladiwala U, Tole S, Vaidya VA . Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis. Eur J Neurosci 2005; 22: 1570–1580.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Watkins CC, Sawa A, Pomper MG . Glia and immune cell signaling in bipolar disorder: insights from neuropharmacology and molecular imaging to clinical application. Transl Psychiatr 2014; 4: e350.

    Article  CAS  Google Scholar 

  61. Li X, Zhu W, Roh MS, Friedman AB, Rosborough K, Jope RS . In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. Neuropsychopharmacology 2004; 29: 1426–1431.

    Article  CAS  PubMed  Google Scholar 

  62. Vila G, Papazoglou M, Stalla J, Theodoropoulou M, Stalla GK, Holsboer F et al. Sonic hedgehog regulates CRH signal transduction in the adult pituitary. FASEB J 2005; 19: 281–283.

    Article  CAS  PubMed  Google Scholar 

  63. Varjosalo M, Taipale J . Hedgehog: functions and mechanisms. Gene Dev 2008; 22: 2454–2472.

    Article  CAS  PubMed  Google Scholar 

  64. Chen MH, Li YJ, Kawakami T, Xu SM, Chuang PT . Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Gene Dev 2004; 18: 641–659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ho KS, Scott MP . Sonic hedgehog in the nervous system: functions, modifications and mechanisms. Curr Opin Neurobiol 2002; 12: 57–63.

    Article  CAS  PubMed  Google Scholar 

  66. Koide T, Hayata T, Cho KW . Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase. Development 2006; 133: 2395–2405.

    Article  CAS  PubMed  Google Scholar 

  67. Corcoran RB, Scott MP . Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 2006; 103: 8408–8413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bijlsma MF, Peppelenbosch MP, Spek CA . A dual role for 7-dehydrocholesterol reductase in regulating Hedgehog signalling? Development 2006; 133: 3951.

    Article  CAS  PubMed  Google Scholar 

  69. Vuksan-Cusa B, Marcinko D, Nad S, Jakovljevic M . Differences in cholesterol and metabolic syndrome between bipolar disorder men with and without suicide attempts. Prog Neuro-psychopharmacol Biol Psychiatr 2009; 33: 109–112.

    Article  CAS  Google Scholar 

  70. Lalovic A, Merkens L, Russell L, Arsenault-Lapierre G, Nowaczyk MJ, Porter FD et al. Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers. Am J Psychiatr 2004; 161: 2123–2126.

    Article  PubMed  Google Scholar 

  71. Must A, Koks S, Vasar E, Tasa G, Lang A, Maron E et al. Common variations in 4p locus are related to male completed suicide. Neuromol Med 2009; 11: 13–19.

    Article  CAS  Google Scholar 

  72. Egeland JA, Sussex JN . Suicide and family loading for affective disorders. JAMA 1985; 254: 915–918.

    Article  CAS  PubMed  Google Scholar 

  73. Hur EM, Zhou FQ . GSK3 signalling in neural development. Nat Rev Neurosci 2010; 11: 539–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 2009; 12: 1390–1397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sheikh A, Alvi AA, Aslam HM, Haseeb A . Hedgehog pathway inhibitors—current status and future prospects. Infect Agent Cancer 2012; 7: 29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the essential function of the AMISH STUDY Psychiatric Board since 1976: Drs Abram M Hostetter, John J Schwab, Jon A Shaw, Jean Endicott and the late Drs James N Sussex and David R Offord. We thank Cleona R Allen for pedigree drafting and editing, Bernadette Warman as graphic artist, Mary F Sweger for progenitor charts, Martha P Hansell for computer consultation and Alma Becker, project phlebotomist, for collection of all EvC blood samples. Our deepest respect and appreciation belongs to Old Order Amish patients and families who participated in this research commencing in 1960. We thank Betty and Irving Brudnick, patient families and organizations, and our own families for their encouragement and support. We are grateful for support from the Case Western Reserve University Amasa B. Ford MD chair of Geriatric Medicine (RAE), the Brudnick Neuropsychiatric Research Institute (EIG; MG), Grants MH93415 (SMP) and HD004147 (EIG), the University of Massachusetts Medical School (EIG; MG), and past support from the Intramural Research Program, NIMH (EIG; MG; SMP), Eli Lilly (SMP; JAE Amish Study) and NIMH Grant MH28287 (JAE Amish Study).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E I Ginns.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ginns, E., Galdzicka, M., Elston, R. et al. Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder. Mol Psychiatry 20, 1212–1218 (2015). https://doi.org/10.1038/mp.2014.118

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.118

This article is cited by

Search

Quick links