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Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees

Molecular Psychiatry volume 7, pages 954–961 (2002)Cite this article

Abstract

Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9–10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT4 receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder.

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Acknowledgements

Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991–98, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, MD, PhD, Marvin Miller, MD, and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280, Theodore Reich, MD, Allison Goate, PhD, and John Rice, PhD; Johns Hopkins University, Baltimore, MD U01 MH46274, J Raymond DePaulo, Jr, MD, Sylvia Simpson, MD, MPH, and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, MD, Diane Kazuba, BA, and Elizabeth Maxwell, MSW. This study was supported by the grant of Research on Brain Science (H12-Brain-006) and the grant for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare, Japan.

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Authors and Affiliations

  1. Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

    T Ohtsuki, H Ishiguro & T Arinami

  2. National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA

    S D Detera-Wadleigh

  3. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan

    T Toyota, K Yamada, K Yoshitsugu, E Hattori & T Yoshikawa

  4. Department of Neuropsychiatry, Hokushin General Hospital, Nagano, Japan

    H Shimizu

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  1. T Ohtsuki
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  2. H Ishiguro
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Correspondence to T Arinami.

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Ohtsuki, T., Ishiguro, H., Detera-Wadleigh, S. et al. Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees. Mol Psychiatry 7, 954–961 (2002). https://doi.org/10.1038/sj.mp.4001133

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