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Molecular Medicine

, Volume 13, Issue 7–8, pp 407–414 | Cite as

Analysis of TBX1 Variation in Patients with Psychotic and Affective Disorders

  • Birgit H. Funke
  • Todd Lencz
  • Christine T. Finn
  • Pamela DeRosse
  • G. David Poznik
  • Alex M. Plocik
  • John Kane
  • John Rogus
  • Anil K. Malhotra
  • Raju Kucherlapati
Proceedings

Abstract

A significant portion of patients with 22q11 deletion syndrome (22q11DS) develop psychiatric disorders, including schizophrenia and other psychotic and affective symptoms, and the responsible gene/s are assumed to also play a significant role in the etiology of nonsyndromic psychiatric disease. The most common psychiatric diagnosis among patients with 22q11DS is schizophrenia, thought to result from neurotransmitter imbalances and also from disturbed brain development. Several genes in the 22q11 region with known or suspected roles in neurotransmitter metabolism have been analyzed in patients with isolated schizophrenia; however, their contribution to the disease remains controversial. Haploinsufficiency of the TBX1 gene has been shown to be sufficient to cause the core physical malformations associated with 22q11DS in mice and humans and via abnormal brain development could contribute to 22q11DS-related and isolated psychiatric disease. 22q11DS populations also have increased rates of psychiatric conditions other than schizophrenia, including mood disorders. We therefore analyzed variations at the TBX1 locus in a cohort of 446 white patients with psychiatric disorders relevant to 22q11DS and 436 ethnically matched controls. The main diagnoses included schizophrenia (n = 226), schizoaffective disorder (n = 67), bipolar disorder (n = 82), and major depressive disorder (n = 29). We genotyped nine tag SNPs in this sample but did not observe significant differences in allele or haplotype frequencies in any of the analyzed groups (all affected, schizophrenia and schizoaffective disorder, schizophrenia alone, and bipolar disorder and major depressive disorder) compared with the control group. Based on these results we conclude that TBX1 variation does not make a strong contribution to the genetic etiology of nonsyndromic forms of psychiatric disorders commonly seen in patients with 22q11DS.

Notes

Acknowledgments

This project was supported by grants HD034980-09 to RK, K23MH001760 to AKM, K01 MH65580 to TL, P30 MH60575 to JK, and a General Clinical Research Center (M01 RR18535). We thank the HPCGG Genotyping core for their fast and excellent service and Dr. Bernice Morrow for providing services to generate lymphoblastoid cell lines and DNA.

References

  1. 1.
    Ryan AK, Goodship JA, Wilson DI, et al. (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J. Med. Genet. 34:798–804.CrossRefGoogle Scholar
  2. 2.
    Goldberg R, Motzkin B, Marion R, Scambler PJ, Shprintzen RJ. (1993) Velo-cardio-facial syndrome: a review of 120 patients. Am. J. Med. Genet. 45:313–9.CrossRefGoogle Scholar
  3. 3.
    Lindsay EA, Goldberg R, Jurecic V, et al. (1995) Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions. Am. J. Med. Genet. 57:514–22.CrossRefGoogle Scholar
  4. 4.
    Shaikh TH, Kurahashi H, Saitta SC, et al. (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9:489–501.CrossRefGoogle Scholar
  5. 5.
    Carlson C, Sirotkin H, Pandita R, et al. (1997) Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am. J. Hum. Genet. 61:620–9.CrossRefGoogle Scholar
  6. 6.
    Baker KD, Skuse DH. (2005) Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group. Br. J. Psychiatry 186:115–20.CrossRefGoogle Scholar
  7. 7.
    Gothelf D, Gruber R, Presburger G, et al. (2003) Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. J. Clin. Psychiatry 64:1163–69.CrossRefGoogle Scholar
  8. 8.
    Gothelf D, Presburger G, Zohar AH, et al. (2004) Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 126:99–105.CrossRefGoogle Scholar
  9. 9.
    Papolos DF, Faedda GL, Veit S, et al. (1996) Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am. J. Psychiatry 153:1541–7.CrossRefGoogle Scholar
  10. 10.
    Murphy KC. (2005) Annotation: velo-cardio-facial syndrome. J. Child Psychol. Psychiatry 46:563–71.CrossRefGoogle Scholar
  11. 11.
    Fine SE, Weissman A, Gerdes M, et al. (2005) Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11.2 deletion syndrome. J. Autism Dev. Disord. 35:461–70.CrossRefGoogle Scholar
  12. 12.
    Bassett AS, Chow EW, AbdelMalik P, Gheorghiu M, Husted J, Weksberg R. (2003) The schizophrenia phenotype in 22q11 deletion syndrome. Am. J. Psychiatry 160:1580–6.CrossRefGoogle Scholar
  13. 13.
    Murphy KC, Jones LA, Owen MJ. (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56:940–5.CrossRefGoogle Scholar
  14. 14.
    Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW. (1992) Late-onset psychosis in the velo-cardio-facial syndrome. Am. J. Med. Genet. 42:141–142.CrossRefGoogle Scholar
  15. 15.
    Murphy KC. (2002) Schizophrenia and velo-cardio-facial syndrome. Lancet 359:426–30.CrossRefGoogle Scholar
  16. 16.
    Mukai J, Liu H, Burt RA, et al. (2004) Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat. Genet. 36:725–31.CrossRefGoogle Scholar
  17. 17.
    Sinibaldi L, De Luca A, Bellacchio E, et al. (2004) Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Hum. Mutat. 24:534–5.CrossRefGoogle Scholar
  18. 18.
    Sanders AR, Rusu I, Duan J, et al. (2005) Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. Mol. Psychiatry 10:353–65.Google Scholar
  19. 19.
    Sun ZY, Wei J, Xie L, et al. (2004) The CLDN5 locus may be involved in the vulnerability to schizophrenia. Eur. Psychiatry 19:354–7.CrossRefGoogle Scholar
  20. 20.
    Ye L, Sun Z, Xie L, et al. (2005) Further study of a genetic association between the CLDN5 locus and schizophrenia. Schizophr. Res. 75:139–41.CrossRefGoogle Scholar
  21. 21.
    Wang H, Duan S, Du J, et al. (2006) Transmission disequilibrium test provides evidence of association between promoter polymorphisms in 22q11 gene DGCR14 and schizophrenia. J. Neural Transm. 113:1551–61.CrossRefGoogle Scholar
  22. 22.
    De Luca A, Conti E, Grifone N, et al. (2003) Association study between CAG trinucleotide repeats in the PCQAP gene (PC2 glutamine/Q-rich-associated protein) and schizophrenia. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 116:32–5.CrossRefGoogle Scholar
  23. 23.
    De Luca A, Pasini A, Amati F, et al. (2001) Association study of a promoter polymorphism of UFD1L gene with schizophrenia. Am. J. Med. Genet. 105:529–33.CrossRefGoogle Scholar
  24. 24.
    Saito T, Guan F, Papolos DF, Rajouria N, Fann CS, Lachman HM. (2001) Polymorphism in SNAP29 gene promoter region associated with schizophrenia. Mol. Psychiatry 6:193–201.CrossRefGoogle Scholar
  25. 25.
    Takase K, Ohtsuki T, Migita O, et al. (2001) Association of ZNF74 gene genotypes with age-at-onset of schizophrenia. Schizophr. Res. 52:161–5.CrossRefGoogle Scholar
  26. 26.
    Finn CT FB, Kikinis Z, Shenton M, Schiripo T. Psychiatric manifestations of velocardiofacial syndrome. In: Morrow EM, Rosenbaum JF, Fava M, Biederman J, editors. Frontiers in Biological Psychiatry in Childhood: Exploring the Relationship among Genes, Brain Development, and the Emergence of Psychopathology. Arlington (VA): American Psychiatric Publishing, Inc. In press.Google Scholar
  27. 27.
    Owen MJ, Craddock N, O’Donovan MC. (2005) Schizophrenia: genes at last? Trends Genet. 21:518–25.CrossRefGoogle Scholar
  28. 28.
    Harrison PJ, Weinberger DR. (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10:40–68.CrossRefGoogle Scholar
  29. 29.
    Collier DA, Li T. (2003) The genetics of schizophrenia: glutamate not dopamine? Eur. J. Pharmacol. 480:177–84.CrossRefGoogle Scholar
  30. 30.
    Efron ML. (1965) Familial hyperprolinemia: report of a second case, associated with congenital renal malformations, hereditary hematuria and mild mental retardation, with demonstration of an enzyme defect. N. Engl. J. Med. 272:1243–54.CrossRefGoogle Scholar
  31. 31.
    Paterlini M, Zakharenko SS, Lai WS, et al. (2005) Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat. Neurosci. 8:1586–94.CrossRefGoogle Scholar
  32. 32.
    Gogos JA, Santha M, Takacs Z, et al. (1999) The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat. Genet. 21:434–9.CrossRefGoogle Scholar
  33. 33.
    Liu H, Heath SC, Sobin C, et al. (2002) Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 99:3717–22.CrossRefGoogle Scholar
  34. 34.
    Li T, Ma X, Sham PC, et al. (2004) Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 129:13–15.CrossRefGoogle Scholar
  35. 35.
    Williams HJ, Williams N, Spurlock G, et al. (2003) Association between PRODH and schizophrenia is not confirmed. Mol. Psychiatry 8:644–5.CrossRefGoogle Scholar
  36. 36.
    Williams HJ, Williams N, Spurlock G, et al. (2003) Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 120:42–6.CrossRefGoogle Scholar
  37. 37.
    Fan JB, Ma J, Zhang CS, et al. (2003) A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population. Neurosci. Lett. 338:252–4.CrossRefGoogle Scholar
  38. 38.
    Axelrod J. (1966) Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol. Rev. 18:95–113.PubMedGoogle Scholar
  39. 39.
    Karayiorgou M, Gogos JA. (2004) The molecular genetics of the 22q11-associated schizophrenia. Brain Res. Mol. Brain Res. 132:95–104.CrossRefGoogle Scholar
  40. 40.
    Liu H, Abecasis GR, Heath SC, et al. (2002) Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 99:16859–64.CrossRefGoogle Scholar
  41. 41.
    Faul T, Gawlik M, Bauer M, et al. (2005) ZDHHC8 as a candidate gene for schizophrenia: analysis of a putative functional intronic marker in case-control and family-based association studies. BMC Psychiatry 5:35.CrossRefGoogle Scholar
  42. 42.
    Otani K, Ujike H, Tanaka Y, et al. (2005) The ZDHHC8 gene did not associate with bipolar disorder or schizophrenia. Neurosci. Lett. 390:166–70.CrossRefGoogle Scholar
  43. 43.
    Saito S, Ikeda M, Iwata N, et al. (2005) No association was found between a functional SNP in ZDHHC8 and schizophrenia in a Japanese case-control population. Neurosci. Lett. 374:21–4.CrossRefGoogle Scholar
  44. 44.
    Glaser B, Moskvina V, Kirov G, et al. (2006) Analysis of ProDH, COMT and ZDHHC8 risk variants does not support individual or interactive effects on schizophrenia susceptibility. Schizophr. Res. 87:21–7.CrossRefGoogle Scholar
  45. 45.
    Glaser B, Schumacher J, Williams HJ, et al. (2005) No association between the putative functional ZDHHC8 single nucleotide polymorphism rs175174 and schizophrenia in large European samples. Biol. Psychiatry 58:78–80.CrossRefGoogle Scholar
  46. 46.
    Rapoport JL, Addington AM, Frangou S, Psych MR. (2005) The neurodevelopmental model of schizophrenia: update 2005. Mol. Psychiatry 10:434–49.CrossRefGoogle Scholar
  47. 47.
    Guy JD, Majorski LV, Wallace CJ, Guy MP. (1983) The incidence of minor physical anomalies in adult male schizophrenics. Schizophr. Bull. 9:571–82.CrossRefGoogle Scholar
  48. 48.
    Waddington JL, Lane A, Scully P, et al. (1999) Early cerebro-craniofacial dysmorphogenesis in schizophrenia: a lifetime trajectory model from neurodevelopmental basis to ‘neuroprogressive’ process. J. Psychiatr. Res. 33:477–89.CrossRefGoogle Scholar
  49. 49.
    Lindsay EA, Baldini A. (2001) Recovery from arterial growth delay reduces penetrance of cardiovascular defects in mice deleted for the DiGeorge syndrome region. Hum. Mol. Genet. 10:997–1002.CrossRefGoogle Scholar
  50. 50.
    Arnold JS, Werling U, Braunstein EM, et al. (2006) Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations. Development 133:977–87.CrossRefGoogle Scholar
  51. 51.
    LaMantia AS. (1999) Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice. Biol. Psychiatry 46:19–30.CrossRefGoogle Scholar
  52. 52.
    Maynard TM, Sikich L, Lieberman JA, LaMantia AS. (2001) Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia. Schizophr. Bull. 27:457–76.CrossRefGoogle Scholar
  53. 53.
    Maynard TM, Haskell GT, Peters AZ, Sikich L, Lieberman JA, LaMantia AS. (2003) A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc. Natl. Acad. Sci. U. S. A. 100:14433–8.CrossRefGoogle Scholar
  54. 54.
    Lindsay EA, Vitelli F, Su H, et al. (2001) Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410:97–101.CrossRefGoogle Scholar
  55. 55.
    Paylor R, Glaser B, Mupo A, et al. (2006) Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc. Natl. Acad. Sci. U. S. A. 103:7729–34.CrossRefGoogle Scholar
  56. 56.
    Meechan DW, Maynard TM, Wu Y, Gopala-krishna D, Lieberman JA, LaMantia AS. (2006) Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome. Mol. Cell Neurosci. 33:412–28.CrossRefGoogle Scholar
  57. 57.
    Sobin C, Kiley-Brabeck K, Karayiorgou M. (2005) Lower prepulse inhibition in children with the 22q11 deletion syndrome. Am. J. Psychiatry 162:1090–9.CrossRefGoogle Scholar
  58. 58.
    Braff DL, Geyer MA, Swerdlow NR. (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.) 156:234–58.CrossRefGoogle Scholar
  59. 59.
    Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL, Hallett M. (1996) Sensorimotor gating in boys with Tourette’s syndrome and ADHD: preliminary results. Biol. Psychiatry 39:33–41.CrossRefGoogle Scholar
  60. 60.
    Swerdlow NR, Karban B, Ploum Y, Sharp R, Geyer MA, Eastvold A. (2001) Tactile prepuff inhibition of startle in children with Tourette’s syndrome: in search of an “fMRI-friendly” startle paradigm. Biol. Psychiatry 50:578–85.CrossRefGoogle Scholar
  61. 61.
    Hoenig K, Hochrein A, Quednow BB, Maier W, Wagner M. (2005) Impaired prepulse inhibition of acoustic startle in obsessive-compulsive disorder. Biol. Psychiatry 57:1153–8.CrossRefGoogle Scholar
  62. 62.
    Paylor R, McIlwain KL, McAninch R, et al. (2001) Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum. Mol. Genet. 10:2645–50.CrossRefGoogle Scholar
  63. 63.
    Long JM, Laporte P, Merscher S, et al. (2006) Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics 7:247–57.CrossRefGoogle Scholar
  64. 64.
    Yamagishi H, Maeda J, Hu T, et al. (2003) Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer. Genes Dev. 17:269–81.CrossRefGoogle Scholar
  65. 66.
    Zhao JH, Curtis D, Sham PC. (2000) Model-free analysis and permutation tests for allelic associations. Hum. Hered. 50:133–9.CrossRefGoogle Scholar
  66. 67.
    Xie X OJ. (1993) Testing linkage disequilibrium between a disease gene and marker loci (abstract). Am. J. Hum. Genet. 53:1107.Google Scholar
  67. 68.
    Barrett JC, Fry B, Maller J, Daly MJ. (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–5.CrossRefGoogle Scholar
  68. 69.
    Gabriel SB, Schaffner SF, Nguyen H, et al. (2002) The structure of haplotype blocks in the human genome. Science 296:2225–9.CrossRefGoogle Scholar
  69. 70.
    Hiroi N, Zhu H, Lee M, et al. (2005) A200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice. Proc. Natl. Acad. Sci. U. S. A. 102:19132–7.CrossRefGoogle Scholar
  70. 71.
    Funke B, Malhotra AK, Finn CT, et al. (2005) COMT genetic variation confers risk for psychotic and affective disorders: a case control study. Behav. Brain Funct. 1:19.CrossRefGoogle Scholar
  71. 72.
    Funke B, Finn CT, Plocik AM, et al. (2004) Association of the DTNBP1 locus with schizophrenia in a U.S. population. Am. J. Hum. Genet. 75:891–8.CrossRefGoogle Scholar
  72. 73.
    Kendler KS. (2005) “A gene for…”: the nature of gene action in psychiatric disorders. Am. J. Psychiatry 162:1243–52.CrossRefGoogle Scholar
  73. 74.
    Bassett AS, Chow EW. (1999) 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biol. Psychiatry 46:882–1.CrossRefGoogle Scholar
  74. 75.
    Sporn A, Addington A, Reiss AL, et al. (2004) 22q11 deletion syndrome in childhood onset schizophrenia: an update. Mol. Psychiatry 9:225–6.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Birgit H. Funke
    • 1
  • Todd Lencz
    • 2
  • Christine T. Finn
    • 1
  • Pamela DeRosse
    • 2
  • G. David Poznik
    • 3
  • Alex M. Plocik
    • 1
  • John Kane
    • 2
  • John Rogus
    • 3
  • Anil K. Malhotra
    • 2
  • Raju Kucherlapati
    • 1
  1. 1.Laboratory for Molecular MedicineHarvard Partners Center for Genetics and GenomicsCambridge, BostonUSA
  2. 2.Psychiatry ResearchThe Zucker Hillside HospitalGlen OaksUSA
  3. 3.Joslin Diabetes CenterBostonUSA

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