Human Genetics

, Volume 117, Issue 6, pp 520–527

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

Authors

  • Masayuki Ide
    • Laboratory for Molecular PsychiatryRIKEN Brain Science Institute
  • Kazuo Yamada
    • Laboratory for Molecular PsychiatryRIKEN Brain Science Institute
  • Tomoko Toyota
    • Laboratory for Molecular PsychiatryRIKEN Brain Science Institute
  • Yoshimi Iwayama
    • Laboratory for Molecular PsychiatryRIKEN Brain Science Institute
  • Yuichi Ishitsuka
    • Laboratory for Molecular PsychiatryRIKEN Brain Science Institute
  • Yoshio Minabe
    • Department of Psychiatry and NeurologyHamamatsu University School of Medicine
  • Kazuhiko Nakamura
    • Department of Psychiatry and NeurologyHamamatsu University School of Medicine
  • Nobutaka Hattori
    • Department of NeurologyJuntendo University School of Medicine
  • Takashi Asada
    • Department of PsychiatryUniversity of Tsukuba School of Medicine
  • Yoshikuni Mizuno
    • Department of NeurologyJuntendo University School of Medicine
  • Norio Mori
    • Department of Psychiatry and NeurologyHamamatsu University School of Medicine
    • Laboratory for Molecular PsychiatryRIKEN Brain Science Institute
Original Investigation

DOI: 10.1007/s00439-005-1342-8

Cite this article as:
Ide, M., Yamada, K., Toyota, T. et al. Hum Genet (2005) 117: 520. doi:10.1007/s00439-005-1342-8

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.

Copyright information

© Springer-Verlag 2005