Abstract for presentation at 11th International Congress of Human Genetics

Genetic Variation of 5-HT Transcription Factors in Affective Disorders

  • Michael Bland, University of Otago, Christchurch School of Medicine and Health Sciences, Dept of Pathology, New Zealand
  • Prof Peter Joyce, University of Otago, Christchurch School of Medicine and Health Sciences, Dept of Psycological Medicine, New Zealand
  • A/Prof Martin Kennedy, University of Otago, Christchurch School of Medicine and Health Sciences, Dept of Pathology, New Zealand

    • Purpose: Dysregulation of the 5-HT neurotransmitter system has long been identified as an important factor in the pathophysiology of depression. Recently, certain transcription factors (e.g. Nkx2-2, Gata2, Lmx1b, and Fev) have been shown to be necessary and sufficient for development of the specific 5-HT neurons that project to the forebrain. Furthermore, in knock-out mice lacking Fev, the resultant defective development of serotonergic neurons leads to a heightened anxiety-like and aggressive behavioural phenotype in adults. This suggests an important role for these genes in behaviour.
    The purpose of our research was to scan for genetic variability in NKX2-2, GATA2, LMX1B and FEV and investigate the relevance of such variability to onset, symptom patterns or treatment outcomes in depressed individuals.
    Methods: Polymorphisms have been detected in promoters of these genes using a combination of denaturing high performance liquid chromatography (DHPLC) and DNA sequencing in a group of 22 individuals in a family study of depression. Frequencies of variants identified will be established in cohorts of depressed patients and functional relevance of variants determined via luciferase gene reporter assays in COS7 and RN46Â (rat 5-HT neuronal) cells.
    Results: No novel coding SNPs were detected in any genes. However, a range of previously unreported promoter polymorphisms were identified in NKX2-2, GATA2 and LMX1B, including a 4bp deletion which alters a putative Smad3 consensus binding site in GATA2. The frequencies and functional relevance of these promoter polymorphisms are being determined in several depressed cohorts.
    Conclusion: Although the coding regions of human serotonergic transcriptions factors appear to be highly conserved, significant variation exists in the regulatory regions of these genes. Given the tendency towards functional significance for a high proportion of brain gene promoter polymorphisms (≥ 30%), it is likely that some variants found in this study will alter gene expression. Such polymorphisms may play an important role in the development of affective disorders such as depression.

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