Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide.
Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.
D000328:Adult; D000818:Animals; D002999:Clone Cells; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D003865:Major Depressive Disorder / Q000453:epidemiology / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D029721:Drosophila Proteins; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D009864:Ontario / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011903:Raphe Nuclei / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000235:genetics*; D044263:Receptors, Serotonin, 5-HT1; D012097:Repressor Proteins / Q000378:metabolism; D013405:Suicide / Q000706:statistics & numerical data; D014157:Transcription Factors; D014162:Transfection; D044465:White People / Q000235:genetics
C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; C485477:Deaf1 protein, Drosophila; C485478:Deaf1 protein, rat; D029721:Drosophila Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA