American Journal of Medical Genetics (Neuropsychiatric Genetics) 105:343±345 (2001)

Brief Research Communication

No Evidence of an Association Between 5HT1BReceptor Gene Polymorphism and Suicide Victimsin a Japanese Population

Naoki Nishiguchi,1 Osamu Shirakawa,1* Hisae Ono,1 Akiyoshi Nishimura,2 Hideyuki Nushida,3

Yasuhiro Ueno,3 and Kiyoshi Maeda1

1Department of Psychiatry and Neurology, Kobe University School of Medicine, Kobe, Japan2Department of Legal Medicine, Shiga University of Medical Science, Ohtsu, Japan3Department of Legal Medicine, Kobe University School of Medicine, Kobe, Japan

Serotonergic systems have been reported tomediate the control of aggression and/orimpulsivity in humans and to be involved insuicidal behavior. Neurochemical studiesshowing serotonergic dysfunction in suicideappear to support the functional alterationof serotonergic systems due to gene poly-morphisms. Knock-out mice of the 5HT1Breceptor gene have been reported to resultin increased aggression. We hypothesizedthat the 5HT1B receptor-mediated seroto-nergic dysfunction was implicated in sui-cide through disinhibition of aggressionand/or impulsivity. To explore this hypoth-esis, we examined the association betweensuicide victims who completed suicide andthe 5HT1B receptor gene G861C polymorph-ism. No signi®cant differences in genotypedistribution and allele frequencies werefound between suicide victims and controls.Though there is the possibility of failing todetect small effects, these results show noevidence of an association between the5HT1B receptor gene G861C polymorphismand suicide victims in a Japanese popula-tion and indicate that it is unlikely that the5HT1B receptor is implicated in the suscept-ibility to suicide. ß 2001 Wiley-Liss, Inc.

KEY WORDS: 5HT1B receptor; suicide vic-tims; association study;aggression; impulsivity

INTRODUCTION

Several lines of evidence suggest that a serotonergicdysfunction is involved in the susceptibility to suicide.Neurobiological studies in suicidal behavior havedemonstrated a low level of 5-hydroxyindoleacetic acid(5-HIAA) in cerebrospinal ¯uid (CSF) [Asberg, 1997]and a blunted prolactin response to fen¯uramine[Malone et al., 1996]. These ®ndings indicate thatserotonergic hypofunction occurs in suicidal behaviorand are explained by factors other than the presence ofpsychiatric disorders [Mann et al., 1999]. One of thefactors is the lethality of the suicide attempt. Aninverse relationship has been reported between thelevel of CSF 5-HIAA and the severity of lifetimeaggression as well [Brown et al., 1982; Goodwin,1986]. As genetic variation may play a role in thecontrol of serotonin turnover [Highly et al., 1993], theselines of evidence appear to support a functionalalteration of serotonergic systems in suicide due togene polymorphisms. Indeed, studies of families, twins,and adoption have shown that genetic factors areinvolved in suicide [Roy et al., 1997]. Schulsinger et al.[1979] proposed that there is a genetic predispositionfor suicide independent of, or additive to, the majorpsychiatric disorders. Moreover, Kety [1986] suggestedthat one genetic factor in suicide may be an inability tocontrol impulsive behavior.

Serotonin 1B (5HT1B) receptors are autoreceptorslocated on serotonergic nerve terminals that areinvolved in the presynaptic regulation of serotoninrelease in the brain [Engel et al., 1986]. 5HT1Breceptor-induced dysregulation of serotonin releasemay be involved in the low level of CSF 5-HIAA shownin suicidal behavior. In addition, mice without the

Grant sponsor: Research Grant for Nervous and MentalDisorders, the Ministry of Health and Welfare, Japan.

*Correspondence to: Osamu Shirakawa, Department of Psy-chiatry and Neurology, Kobe University School of Medicine, 7-5-1Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.E-mail: sirakawa@kobe-u.ac.jp

Received 25 October 2000; Accepted 13 February 2001

Published online 24 April 2001

ß 2001 Wiley-Liss, Inc.

5HT1B receptor gene were found to have enhancedaggressive behavior [Saudou et al., 1994]. Lappalainenet al. [1998] reported that the 5HT1B receptor gene islinked to antisocial alcoholism and suggested that5HT1B receptors may be involved in the control ofaggression and impulsivity in humans. An inability tocontrol aggression and/or impulsivity caused by 5HT1Breceptor-induced serotonergic dysfunction may resultin suicidal behavior. We hypothesized that 5HT1Breceptors are genetically involved in suicidal behaviorthrough the disinhibition of aggression and/or impul-sivity.

5HT1B is a short (1,137 bp) and intronless gene [Levyet al., 1992; Weinshank et al., 1992] with two commonpolymorphisms in the coding region, C129T and G861C[Sidenberg et al., 1993; Lappalainen et al., 1995; Huanget al., 1999]. These two polymorphisms are silent,which is thought to have no functional consequence tothe protein, and have been reported to be in totallinkage disequilibrium [Huang et al., 1999]. To explorethe hypothesis that the 5HT1B receptor is involved inserotonergic dysfunction in suicide, we focused on theG861C polymorphism of the 5HT1B receptor gene andexamined the association between suicide victims whocomplete suicide and the G861C polymorphism.

MATERIALS AND METHODS

This study was conducted in accordance with theethical code of the Japanese Society of Legal Medicine.The study population consisted of 163 suicide victims(113 males and 50 females; mean age�SD, 47.9�17.6years) who completed suicide and on whom autopsieswere conducted in the Department of Legal Medicine,Kobe University School of Medicine. Suicide methodswere classi®ed as violent or nonviolent according toHeilaÈ et al. [1997]. Of the suicide victims, 142 were doneby violent methods (i.e., hanging, jumping from a highplace, cutting, burning, and jumping under a vehicle)and 21 were done by nonviolent methods (i.e., drugoverdose, drowning, and inhaling carbon monoxide).The controls consisted of 163 unrelated volunteers (113males and 50 females; mean age�SD, 44.7�14.9 years).All subjects were ethnically Japanese.

Peripheral blood was drawn from suicide victims andcontrols, and leukocyte DNA was extracted for geno-type determination. The genotype of the 5HT1Breceptor gene G861C polymorphism was determinedby the method of Lappalainen et al. [1998]. Differencesin the genotype and allele frequencies of the 5HT1Breceptor gene G861C polymorphism between suicidevictims and control subjects were tested for signi®canceusing a chi-square test. Probability differences ofP<0.05 were considered statistically signi®cant.

RESULTS AND DISCUSSION

The frequency of the G-allele of the G861C poly-morphism of the 5HT1B receptor gene was 0.51 incontrol subjects. A previous study found G-allelefrequencies of this polymorphism of 0.76 in a Finnishpopulation and 0.40 in a southwestern AmericanIndian tribe [Lappalainen et al., 1998]. Thus, the allele

frequencies of the G861C polymorphism in these twopopulations and in the present Japanese population areconsiderably different.

The distribution of genotypes in our sample was inHardy-Weinberg equilibrium. As shown in Table I, wedetected no difference in the allele and genotypefrequencies of the 5HT1B receptor G861C polymorph-ism between suicide victims who completed suicide andcontrols. Huang et al. [1999], who conducted apostmortem brain study of suicide and nonsuicidegroups, found no differences in genotype distributionor allelic frequency of the G861C polymorphismbetween the two groups. The number of their studywas relatively small (the number of suicides andnonsuicides were 71 and 107, respectively) and thenonsuicides were possibly somewhat different from thecontrol subjects of this study, because their nonsuicidegroup contained homicide and motor vehicle accidentsas the cause of death. Our study con®rmed the resultsof their study and developed the evidence that theG861C of the 5HT1B receptor is not likely to beassociated with suicide. Though genetic variationswere screened in the coding region of the 5HT1Breceptor gene in a Japanese population, no polymorph-isms with the change of amino acid sequence weredetected [Ohara et al., 1996]. Thus, we concluded that itis as yet unlikely that the 5HT1B receptor is implicatedin the susceptibility to suicide in a Japanese popula-tion.

Assuming chi-square analysis, this study would havesubstantial power (> 0.99) to detect difference of amedium (w� 0.3) [Cohen, 1988] effect size. However,assuming a low (w� 0.1) effect size, the power is only0.44 (genotype) and 0.35 (alleles), respectively. Thismeans that the present study may fail to detect smalleffects due to a type II error.

Furthermore, because the 5HT1B receptor is thoughtto be involved in aggression and/or impulsivity, wecompared the genotype and allele frequencies of theG861C polymorphism between the male suicide victimsand male controls and between suicide victims whocommitted suicide by violent methods and controls. Nosigni®cant differences were found in the genotypedistribution or allele frequencies between either ofthese groups and the controls (data not shown). These

TABLE I. Genotype and Allele Frequencies of 5HT1B ReceptorGene G861C Polymorphism in Japanese Suicide Victims Who

Completed Suicide and Controls*

Suicide victims(n� 163)

Controls(n�163)

GenotypeG/G 44 (27.0%) 38 (23.3%)G/C 73 (44.8%) 89 (54.6%)C/C 46 (28.2%) 36 (22.1%)

AlleleG 161 (49.4%) 165 (50.6%)C 165 (50.6%) 161 (49.4%)

*No signi®cant differences were found between the suicide victims and thecontrols in either the genotype distribution Chi square �3.239; df�2;P� 0.198) or the allele frequencies (Chi square�0.098; df�1; P�0.754).

344 Nishiguchi et al.

®ndings indicated that the 5HT1B receptor gene isunlikely to be involved in aggression and/or impulsivitythat are associated with suicide.

As mentioned earlier, suicide may have a geneticcomponent that is independent of psychiatric disorders.Therefore, it seems useful to investigate genetic factorsin suicide victims who completed suicide, such as thesubjects in this study. The samples collected in thisstudy can be used to identify other genes in theserotonergic systems to clarify the genetic contribu-tions of serotonin in suicide.

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