Distinguishable Haplotype Blocks in the HTR3A and HTR3B Region in the Japanese Reveal Evidence of Association of HTR3B with Female Major Depression

BACKGROUND Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. METHODS To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. RESULTS Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples. In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. CONCLUSIONS Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese.

[1]  Kazuo Yamada,et al.  Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders , 2004, Biological Psychiatry.

[2]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[3]  F. Dudbridge.  Pedigree disequilibrium tests for multilocus haplotypes , 2003, Genetic epidemiology.

[4]  C. Glass,et al.  The Pharmacological and Functional Characteristics of the Serotonin 5-HT3A Receptor Are Specifically Modified by a 5-HT3B Receptor Subunit* , 1999, The Journal of Biological Chemistry.

[5]  T. Nakajima,et al.  [Serotonin (5-HT)]. , 1978, Nihon rinsho. Japanese journal of clinical medicine.

[6]  G Kalsi,et al.  Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23. , 2001, American journal of human genetics.

[7]  J. A. van Hooft,et al.  5-HT3 receptors in the CNS: 3B or not 3B? , 2003, Trends in pharmacological sciences.

[8]  L. Siever,et al.  Genome scan of schizophrenia. , 1998, The American journal of psychiatry.

[9]  A. Lin,et al.  Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus , 2001, Neuropharmacology.

[10]  L R Goldin,et al.  A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Morales,et al.  Differential Composition of 5-Hydroxytryptamine3Receptors Synthesized in the Rat CNS and Peripheral Nervous System , 2002, The Journal of Neuroscience.

[12]  John A. Peters,et al.  The 5-HT3B subunit is a major determinant of serotonin-receptor function , 1999, Nature.

[13]  M. Rietschel,et al.  Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. , 2001, Pharmacogenetics.

[14]  M. James,et al.  Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree. , 1998, American journal of medical genetics.

[15]  Lars-Göran Nilsson,et al.  A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women. , 2003, Archives of general psychiatry.

[16]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[17]  J. Pritchard,et al.  Use of unlinked genetic markers to detect population stratification in association studies. , 1999, American journal of human genetics.

[18]  J. Kapeller,et al.  Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E. , 2003, Gene.

[19]  Kazuo Yamada,et al.  Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders , 2003, Neuroscience Letters.

[20]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.

[21]  J. Yakel,et al.  Serotonin 5‐HT3 receptors in rat CA1 hippocampal interneurons: functional and molecular characterization , 2002 .

[22]  S. Mochizuki,et al.  Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species. , 1995, Molecular pharmacology.

[23]  P. Bork,et al.  Human non-synonymous SNPs: server and survey. , 2002, Nucleic acids research.

[24]  Daniel Hoyer,et al.  Molecular, pharmacological and functional diversity of 5-HT receptors , 2002, Pharmacology Biochemistry and Behavior.

[25]  E. Frank,et al.  Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. , 2000, Archives of general psychiatry.

[26]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[27]  E. Cook,et al.  Sex-specific genetic architecture of whole blood serotonin levels. , 2005, American journal of human genetics.

[28]  Margot Albus,et al.  Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[29]  E. Hattori,et al.  Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts , 2004, Biological Psychiatry.

[30]  C Caron,et al.  Linkage results on 11Q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia. , 1995, American journal of medical genetics.

[31]  J. Schaeffer,et al.  Estrogen receptor-β regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe , 2005, Biological Psychiatry.

[32]  F. Holsboer,et al.  Functional antagonistic properties of clozapine at the 5-HT3 receptor. , 1996, Biochemical and biophysical research communications.

[33]  J. Fawcett,et al.  Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. , 1998, Journal of affective disorders.

[34]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.