Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in japanese case-control samples and the nimh genetics initiative bipolar pedigrees

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

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access 25 January 2022 POSITIONAL CLONING AND COMPREHENSIVE MUTATION ANALYSIS OF A JAPANESE FAMILY WITH LITHIUM-RESPONSIVE BIPOLAR DISORDER IDENTIFIES A NOVEL _DOCK5_ MUTATION Article 12

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medical Genetics, Institute of Basic Medical

Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan T Ohtsuki, H Ishiguro & T Arinami * National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA S D

Detera-Wadleigh * Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan T Toyota, K Yamada, K Yoshitsugu, E Hattori & T Yoshikawa * Department of

Neuropsychiatry, Hokushin General Hospital, Nagano, Japan H Shimizu Authors * T Ohtsuki View author publications You can also search for this author inPubMed Google Scholar * H Ishiguro View

author publications You can also search for this author inPubMed Google Scholar * S D Detera-Wadleigh View author publications You can also search for this author inPubMed Google Scholar *

T Toyota View author publications You can also search for this author inPubMed Google Scholar * H Shimizu View author publications You can also search for this author inPubMed Google Scholar

* K Yamada View author publications You can also search for this author inPubMed Google Scholar * K Yoshitsugu View author publications You can also search for this author inPubMed Google

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation *

Received: 07 January 2002 * Accepted: 04 March 2002 * Published: 25 October 2002 * Issue Date: 01 October 2002 * DOI: https://doi.org/10.1038/sj.mp.4001133 SHARE THIS ARTICLE Anyone you

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Springer Nature SharedIt content-sharing initiative KEYWORDS * _HTR4_ * schizophrenia * affective disorder * polymorphism * haplotype * transmission disequilibrium test * association