title: Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease.
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 beta-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 x 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.
authors: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan.
authors: Masayuki
authors: M
authors: Ide
authors: Kazuo
authors: K
authors: Yamada
authors: Tomoko
authors: T
authors: Toyota
authors: Yoshimi
authors: Y
authors: Iwayama
authors: Yuichi
authors: Y
authors: Ishitsuka
authors: Yoshio
authors: Y
authors: Minabe
authors: Kazuhiko
authors: K
authors: Nakamura
authors: Nobutaka
authors: N
authors: Hattori
authors: Takashi
authors: T
authors: Asada
authors: Yoshikuni
authors: Y
authors: Mizuno
authors: Norio
authors: N
authors: Mori
authors: Takeo
authors: T
authors: Yoshikawa
mesh_terms: D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins; D001714:Bipolar Disorder / Q000235:genetics; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D010455:Peptides; D014157:Transcription Factors; C065500:ASCL1 protein, human; C109220:NBPhox protein; C097188:polyglutamine