Skip to main content
SpringerLink
Log in

Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson’s disease

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

We previously identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PHOX2B (PMX2B), the gene for a transcription factor that plays important roles in the development of oculomotor nerves and catecholaminergic neurons and regulates the expression of both tyrosine hydroxylase and dopamine β-hydroxylase genes. An association was detected between gene polymorphisms and overall schizophrenia, and more specifically, schizophrenia with ocular misalignment. These prior results implied the existence of other schizophrenia susceptibility genes that interact with PHOX2B to increase risk of the combined phenotype. ASCL1 was considered as a candidate interacting partner of PHOX2B, as ASCL1 is a transcription factor that co-regulates catecholamine-synthesizing enzymes with PHOX2B. The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes. These phenotypes included not only schizophrenia, but also bipolar affective disorder and Parkinson’s disease (PD), each of which involve catecholaminergic function. The current case-control analyses detected nominal associations between polyglutamine length variations in ASCL1 and PD (P=0.018), but supported neither the previously observed weak association between PHOX2B and general schizophrenia, nor other gene-disease correlations. Logistic regression analysis revealed the effect of ASCL1 dominant × PHOX2B additive (P=0.008) as an epistatic gene–gene interaction increasing risk of PD. ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD. The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2a–c

Similar content being viewed by others

References

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, D.C.

  • Bing G, Zhang Y, Watanabe Y, McEwen BS, Stone EA (1994) Locus coeruleus lesions potentiate neurotoxic effects of MPTP in dopaminergic neurons of the substantia nigra. Brain Res 668:261–265

    PubMed  Google Scholar 

  • Brownstein MJ, Carpten JD, Smith JR (1996) Modulation of non-templated nucleotide addition by Taq DNA polymerase: primer modifications that facilitate genotyping Biotechniques 20:1004–1006, 1008–1010

  • Cordell HJ, Clayton DG (2002) A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 70:124–141

    PubMed  Google Scholar 

  • De Pontual L, Nepote V, Attie-Bitach T, Al Halabiah H, Trang H, Elghouzzi V, Levacher B, Benihoud K, Auge J, Faure C, Laudier B, Vekemans M, Munnich A, Perricaudet M, Guillemot F, Gaultier C, Lyonnet S, Simonneau M, Amiel J (2003) Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine’s curse). Hum Mol Genet 12:3173–3180

    PubMed  Google Scholar 

  • Dekker MC, Bonifati V, Van Duijn CM (2003) Parkinson’s disease: piecing together a genetic jigsaw. Brain 126:1722–1733

    PubMed  Google Scholar 

  • Fornai F, Alessandri MG, Torracca MT, Bassi L, Corsini GU (1997) Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions. J Pharmacol Exp Ther 283:100–107

    PubMed  Google Scholar 

  • Gesi M, Soldani P, Giorgi FS, Santinami A, Bonaccorsi I, Fornai F (2000) The role of the locus coeruleus in the development of Parkinson’s disease. Neurosci Biobehav Rev 24:655–668

    PubMed  Google Scholar 

  • Hattori N, Kobayashi H, Sasaki-Hatano Y, Sato K, Mizuno Y (2003) Familial Parkinson’s disease: a hint to elucidate the mechanisms of nigral degeneration. J Neurol 250(Suppl 3):III2–10

    PubMed  Google Scholar 

  • Itokawa M, Yamada K, Yoshitsugu K, Toyota T, Suga T, Ohba H, Watanabe A, Hattori E, Shimizu H, Kumakura T, Ebihara M, Meerabux JMA, Toru M, Yoshikawa T (2003) A microsatellite repeat in the promoter of the NMDA receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. Pharmacogenetics 13:271–278

    PubMed  Google Scholar 

  • Lipinski MM, Yuan J (2004) Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol 4:85–90

    PubMed  Google Scholar 

  • Ludecke B, Knappskog PM, Clayton PT, Surtees RA, Clelland JD, Heales SJ, Brand MP, Bartholome K, Flatmark T (1996) Recessively inherited L-DOPA-responsive Parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. Hum Mol Genet 5:1023–1028

    PubMed  Google Scholar 

  • Marder K, Tang MX, Mejia H, Alfaro B, Cote L, Louis E, Groves J, Mayeux R (1996) Risk of Parkinson’s disease among first-degree relatives: a community-based study. Neurology 47:155–160

    PubMed  Google Scholar 

  • Mavridis M, Degryse AD, Lategan AJ, Marien MR, Colpaert FC (1991) Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson’s disease. Neuroscience 41:507–523

    PubMed  Google Scholar 

  • Ott J (2001) Neural networks and disease association studies. Am J Hum Genet 105:60–61

    Google Scholar 

  • Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1997) Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development 124:4065–4075

    PubMed  Google Scholar 

  • Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1999) The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 399:366–370

    PubMed  Google Scholar 

  • Pattyn A, Goridis C, Brunet JF (2000) Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Mol Cell Neurosci 15:235–243

    PubMed  Google Scholar 

  • Renault B, Lieman J, Ward D, Krauter K, Kucherlapati R (1995) Localization of the human achaete-scute homolog gene (ASCL1) distal to phenylalanine hydroxylase (PAH) and proximal to tumor rejection antigen (TRA1) on chromosome 12q22-q23. Genomics 30:81–83

    PubMed  Google Scholar 

  • Schneider RD, Excofier L (2000) Arlequin: a software for population genetics data analysis, 2 edn, version 2.000. Genetics and Biometry Laboratory, Department of Anthropology, University of Geneva

  • Sham PC, Curtis D (1995) Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 59:97–105

    PubMed  Google Scholar 

  • Srinivasan J, Schmidt WJ (2004) Treatment with alpha2-adrenoceptor antagonist, 2-methoxy idazoxan, protects 6-hydroxydopamine-induced Parkinsonian symptoms in rats: neurochemical and behavioral evidence. Behav Brain Res 154:353–363

    PubMed  Google Scholar 

  • Sriuranpong V, Borges MW, Strock CL, Nakakura EK, Watkins DN, Blaumueller CM, Nelkin BD, Ball DW (2002) Notch signaling induces rapid degradation of achaete-scute homolog 1. Mol Cell Biol 22:3129–3139

    PubMed  Google Scholar 

  • Toyota T, Yoshitsugu K, Ebihara M, Yamada K, Ohba H, Fukasawa M, Minabe Y, Nakamura K, Sekine Y, Takei N, Suzuki K, Itokawa M, Meerabux JMA, Iwayama-Shigeno Y, Tomaru Y, Shimizu H, Hattori E, Mori N, Yoshikawa T (2004) Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet 13:551–561

    PubMed  Google Scholar 

  • Warner TT, Schapira AH (2003) Genetic and environmental factors in the cause of Parkinson’s disease. Ann Neurol 53 (Suppl 3):S16–S23

    PubMed  Google Scholar 

  • Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by RIKEN BSI Funds, Research on Brain Science Funds from the Ministry of Health Labor and Welfare, CREST funds from the Japan Science and Technology Agency and grants from the MEXT of Japan. We wish to thank Ms Ohba for technical assistance and the members of the Research Resource Center at the RIKEN Brain Science Institute for genotyping services.

Author information

Authors and Affiliations

  1. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan

    Masayuki Ide, Kazuo Yamada, Tomoko Toyota, Yoshimi Iwayama, Yuichi Ishitsuka & Takeo Yoshikawa

  2. Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan

    Yoshio Minabe, Kazuhiko Nakamura & Norio Mori

  3. Department of Neurology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan

    Nobutaka Hattori & Yoshikuni Mizuno

  4. Department of Psychiatry, University of Tsukuba School of Medicine, Ibaraki, 305-8576, Japan

    Takashi Asada

Authors
  1. Masayuki Ide
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuo Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoko Toyota
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshimi Iwayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuichi Ishitsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoshio Minabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhiko Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobutaka Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Asada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshikuni Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Norio Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takeo Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeo Yoshikawa.

Additional information

M. Ide and K. Yamada contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ide, M., Yamada, K., Toyota, T. et al. Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson’s disease. Hum Genet 117, 520–527 (2005). https://doi.org/10.1007/s00439-005-1342-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-005-1342-8

Keywords

Search

Navigation