A common polymorphism in the 3′-UTR of the NOS1 gene was associated with completed suicides in Japanese male population

8/3/2019 A common polymorphism in the 3-UTR of the NOS1 gene was associated with completed suicides in Japanese mal

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A common polymorphism in the 3-UTR of the NOS1 gene was associated with

completed suicides in Japanese male population

Huxing Cui a, Irwan Supriyanto a, Migiwa Asano b, Yasuhiro Ueno b, Yasushi Nagasaki c, Naoki Nishiguchi d,Osamu Shirakawa d, Akitoyo Hishimoto a,a Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japanb Department of Legal Medicine, Kobe University Graduate School of Medicine, Japanc Hyogo Medical Examiner's Office, Kobe, Japand Department of Neuropsychiatry, Kinki University School of Medicine, Osaka, Japan

a b s t r a c ta r t i c l e i n f o

Article history:

Received 22 February 2010

Received in revised form 5 April 2010

Accepted 27 April 2010

Available online 12 May 2010

Keywords:

Aggression

Impulsivity

Neuronal nitric oxide synthase

NOS1

Polymorphism

Suicide

Background: Suicidal behavior has been widely accepted as familial. Its transmission cannot be explained by

the transmission of psychiatric disorder alone and seems to be partly explained by the transmission of

impulsiveaggressive behavior. Studies in laboratory animal have shown that mice lacking NOS1 manifest

significant aggressive behavior. Further, several polymorphisms of neuronal nitric oxide synthase (NOS1)

gene have been reported to be associated with impulsivity, aggression and suicide attempts. To further

clarify the possible involvement of NOS1 with suicide, we carried out an association study of NOS1 gene

polymorphisms with completed suicide.

Methods: We examined 7 single nucleotide polymorphisms (SNPs) of the NOS1 gene which were previously

studied in several neuropsychiatric disorders (rs2682826, rs6490121, rs3782206, rs561712, rs3782219,

rs3782221, and rs41279104), in age and gender matched 287 healthy control subjects and 284 completed

suicides using the TaqMan probe assays.

Results: We found that both the genotypic distribution and the allelic frequencies of rs2682826 SNP were

significantly different between the completed suicide and control groups (P=0.0007 and 0.0005,

respectively). The odd ratio for the minor allele of the SNP was 0.653 (95% CI 0.513

0.832). The significancewas remained even after correction for multiple testing. Gender-based analysis showed that the significances

were appeared in males only.

Conclusion: Our study raises a possibility that a genetic variation of NOS1 may be implicated in the

pathophysiology of suicide in Japanese population, especially in males. Further studies on more NOS1 genetic

variants are needed to confirm our observations.

2010 Elsevier Inc. All rights reserved.

1. Introduction

Suicide is a major public health problem and is one of the leading

causes of death in young age groups and particularly in psychiatric

patients (WHO, 2005). Both genetic and environmental factors likely

playa crucialrole in the pathogenesisof suicide (Brent and Mann, 2005;

WHO, 2005). Genetic inheritance for suicide attempt and completed

suicide has been demonstrated by family, twin and adoption studies

(Roy et al., 1997). Even though 90% of suicide victims or suicide

attempters have a diagnosable psychiatric illness (Robins et al., 1959;

Beautrais et al., 1996; Shaffer et al., 1996; Van Heeringen, 2003), most

patients never attempt suicide, indicating a predisposition to suicidal

behavior thatis independent from themain psychiatric disorder (Mann,

1998, 2003; Rujescu et al, 2007; Ernst et al, 2009).

Accumulating evidences suggest that certain abnormal emotional

traits, such as impulsive aggression and cluster B personality, are also

associated with suicidal behavior (Turecki, 2005; Rujescu et al., 2007;

Currier and Mann, 2008; Mann et al., 2009). Higher level of impulsive

aggression appeared to be related to familial loading of suicidal

behavior and increased suicide risk among patients of the same

psychiatric disorder (Dumais et al, 2005; Ernst et al., 2009; McGirr

et al., 2009). Familial aggregation of suicidal behavior seems to be

partly explained by the transmission of impulsive aggressive behavior

and cluster B personality traits (Ernst et al, 2009; McGirr et al, 2009).

Thus, genetic factors affecting such emotional traits could possibly be

involved in suicidal behavior as well.

Nitric oxide (NO), a pleiotropic gaseous neurotransmitter, is

mainly produced by neuronal nitric oxide synthase (NOS1) in the

Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 992996

Abbreviations: CNS, central nervous system; DSM-IV, Diagnostic and Statistical

Manual of Mental Disorders 4th edition; HWE, Hardy Weinberg equilibrium; LD,

linkage disequilibrium; NO, nitric oxide; NOS1, nitric oxide synthase 1; SNP, single

nucleotide polymorphism.

Corresponding author. Department of Psychiatry, Faculty of Medical Science, Kobe

University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017,

Japan. Tel.: +81 78 382 6065; fax: +81 78 382 6079.

E-mail address: [email protected] (A. Hishimoto).

0278-5846/$ see front matter 2010 Elsevier Inc. All rights reserved.

doi:10.1016/j.pnpbp.2010.04.028

Contents lists available at ScienceDirect

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central nervous system (Snyder and Ferris, 2000; Baranano et al.,

2001). Seemingly in consistent with its various neurobiological

function, numerous neurobiochemical studies to date have shown

that nitrergic dysfunction seems to be involved in several neuropsy-

chiatric disorders, such as schizophrenia (Shinkai et al., 2002),

Alzheimer's disease (Galimberti et al., 2008), major depression and

suicidal behavior as well (Rujescu et al., 2008). The possible

involvement of NOS1 in suicidal behavior arises from a set of

evidences. First, studies in laboratory animals have shown thatmale mice lacking NOS1 exhibited a significantly increased impul-

sive aggression and abnormal social behavior concomitant with

altered 5-HT signalling (Nelson et al., 1995; Demas et al., 1999;

Chiavegatto et al., 2001; Tanda et al., 2009), which have been broadly

postulated in association with suicidal behavior. Second, NOS1protein

level has been reported to be decreased in the locus coeruleus

of postmortem brain of suicide committed-depressive subjects

(Karolewicz et al., 2004). Third, most importantly, some of the NOS1

gene variants and its haplotypes have been reported to be associated

with impulsive aggression (Reif et al., 2009) and suicide attempts

(Rujescu et al., 2008).

Based upon these previous findings, we decided to further test

possible involvement of NOS1 in completed suicide and carried out an

association study between seven SNP markers of the NOS1 gene and

suicide victims in a total of 571 Japanese sample.

2. Materials and methods

2.1. Subjects

The study population consisted of 284 completed suicides (193

males: mean ageSD, 48.9 16.4; 91 females: 46.9 19.5) on whom

autopsies were conducted at the Department of Legal Medicine, Kobe

University Graduate School of Medicine. All subjects were of Japan

descent. Because accurate information about the clinical backgrounds

of the completed suicides could not be obtained under our ethical

code for genetic studies and because the information about the

occurrence of psychopathologies prior to death was availableonly in a

small proportion of subjects, these data were not presented here. Thesuicide methods are neck hanging (140), jumping from heights (65),

drowning (10), drug overdose (8), cutting/stabbing with sharp

objects (7), gas suffocation (6), jumping in front of vehicles (4), self

burning (4), drinking poison (1), and others (5). We consider neck

hanging, jumping from heights, cutting/stabbing with sharp objects,

jumping in front of vehicles, and self burning as violent methods as

described by Giegling et al (2009). The control consisted of 287

unrelated healthy subjects (185 males: mean ageSD, 47.218.7;

102 females: 53.6 14.3). None of them manifested psychiatric

problems in unstructured interview using the Diagnostic and

Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria

conducted by two psychiatrists. All of the control subjects were

checked for a history and family history of psychiatric disorders and

suicidal behaviours. All subjects were of Japan descent and recruitedfrom the main islands of Japan, with consent after the purpose and

procedures of the study were explained. This study was approved by

the Ethical Committee for Genetic Studies of Kobe University

Graduate School of Medicine.

2.2. SNP selection

Seven SNPs in the NOS1 gene were selected (rs2682826,

rs6490121, rs3782206, rs561712, rs3782219, rs3782221, and

rs41279104) based on minor allele frequency above 10% based on

previous reports, and were shown by several studies to have

association with psychiatric disorders (Shinkai et al., 2002; Fallin

et al., 2005; Rujescu et al., 2008; Tang et al., 2008; Okumura et al.,

2009).

2.3. SNP genotyping

DNA was extracted from peripheral blood samples of the suicide

victims and controls. We genotyped the seven SNP markers by

TaqMan probe assays. We selected the pre-designed TaqMan SNP

genotyping assays from the Applied Biosystems database (http://

www.appliedbiosystems.com) for rs2682826, rs6490121, rs3782206,

rs561712,rs3782219, and rs3782221, and a made to order probe from

Applied Biosystems for rs41279104. The TaqMan reaction wasperformed in a final volume of 5 l with the Universal Master Mix

(Applied Biosystems, Foster City, CA, USA), and genotyping was

performed with a 7500 Real Time PCR System (Applied Biosystems,

Foster City, CA, USA).

2.4. Data analysis

We used theHaploview software program version 4.1 (Barret et al,

2005) (http://www.broad.mit.edu/mpg/haploview) to determine the

HardyWeinberg equilibrium (HWE), linkage disequilibrium (LD),

and allelic/haplotype frequencies, as well as the association between

SNPs of the control and completed suicide. Permutation tests on

10,000 replications were also performed to calculate corrected

p values for multiple testing by the Haploview software, if required.

Genotype-based association was tested with CochranArmitage test

for trend. The study power analysis was performed with the PS

v2.1.31 software (Dupont and Plummer, 1998). Odd ratio and 95%

confident interval (CI) analyses, and unpaired t-tests were performed

using SPSS software (SPSS version 15 for windows, IL, USA). Unpaired

t-tests were performed to match the age of each group. Statistical

significance was defined at pb0.05.

3. Results

No statistically significant differences were observed between the

completed suicide and control groups for the mean values of age

(t=0.828, df=569.0, p =0.41). Distribution of all seven SNPs in each

group did not differ from HWE. We found 2 tight LD blocks of

rs3782206rs561712 SNPs (d=0.882; r2=0.055) and rs3782219rs3782221 SNPs (d=0.978; r2=0.554) using the four gamete rule

analysis.

A statistically significant difference was observed between the

completed suicide and control groups in both genotypic distribution

(nominally p =0.0007) and allelic frequency (nominally p =0.0005,

corrected p =0.0031) only for the rs2682826 SNP (Table 1). The

frequency of the minor T allele of rs2682826 SNP in the completed

suicide group was lower than the control group (minor allele

frequency 0.324 and 0.423, respectively). The odds ratio for

rs2682826 SNP is 0.65 (95% CI 0.510.83). Interestingly, gender-

based analysis revealed that this significance was mainly attributed to

males (genotypic nominally p =0.0003, allelic nominally p =0.0002,

and corrected allelic p =0.0013) (Table 1). The odds ratio for

rs2682826 SNP was 0.575 (95% CI 0.4270.773) in the males and0.836 (95% CI 0.5501.272) in the females. Based on observed allele

frequency of the rs2682826 SNP, the current samples yielded a power

of 0.69 for the detection of nominally significant results.

Additionally, we compared the genotypic and allelic distribution

between 220 completed suicides with violent methods and matched

controls for rs2682826 SNP. We observed the similar results in the

overall analyses and gender base analyses (Table 2).

4. Discussion

We here report an association of the rs2682826 SNP of NOS1 gene

with completed suicide in Japanese population. Both genotypic

distribution and allelic frequency of the rs2682826 SNP were

significantly different between the completed suicide and control

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groups even after correction for multiple testing. Along with the

previous association study (Rujescu et al., 2008), our results provide

further evidence to support the hypothesis that NOS1 is a biological

susceptibility gene to suicide, especially in males.

NOS1 gene is located on chromosome 12q24.2 and consists of 29

exons and 28 introns, encompassing more than 160 kb of genomic

DNA (Hall et al., 1994). The rs2682826 SNP is located in the 3-UTR of

exon 29 of NOS1 gene and has been suggested to be associated with

suicide attempts (Rujescu et al, 2008) and schizophrenia (Shinkai

et al, 2002). Given the known function of 3-UTR in degenerativestability and translational efficiency of mRNA (Mignone et al., 2002;

Chatterjee and Pal, 2009), we cannot exclude a possibility that

rs2682826 SNP may be functionally important. Alternatively, another

possible explanation is that some unknown functional variants

somewhere in the NOS1 gene are linked to rs2682826 SNP and

influence NOS1 expression level in vivo. Further functional analyses,

detailed mutation screening and more systemic association studies

are needed to clarify these possibilities.

The SNPs chosen in the present study were based on some

previous association studies that showed significant association of

these SNPs with schizophrenia and bipolar disorder (Shinkai et al.,

2002; Fallin et al., 2005; Tang et al., 2008; Okumura et al., 2009 ), but

not rigorously based on criteria for tag SNP selection for the whole

gene locus. Therefore, we thought that haplotype analysis in seven

SNP markers studied in the present study is inappropriate. It has

been firstly reported by Rujescu et al (2008) that the CGG

haplotype which consists of 3 SNPs of NOS1 gene including

rs2682826 SNP (rs2682826rs1353939rs693534 SNPs) was signif-

icantly associated with suicidal behavior especially suicide attempts.

We could not analyze the same CGG haplotype in the present

study because rs1353939 and rs693534 SNPs were out of our study.Future association studies with more systemic SNPs selection are

thought to be needed to clarify the involvement of NOS1 in suicidal

behavior.

NOS1 is the main NO synthesizing enzyme in the central nervous

system (CNS) (Snyder and Ferris, 2000; Baranano et al., 2001). As a

diffusible pleiotropic gaseous neurotransmitter, NO has many faces of

neurophysiological function in the brain including modulation of

several conventional neurotransmitter's pathways such as serotonin

(Chiavegatto and Nelson, 2003), a pathway that has been extensively

studied and believed to be involved in the pathogenesis of suicidal

behavior (Mann et al, 2001).

Table 1

Association study between NOS1 gene and suicide.

SNP IDa Positiona Phenotypeb MAFc Genotype distributiond p value

M/M M/m m/m HWEe Genotypef Alleleg

rs41279104 8446994 SCD 0.170 192 86 5 0.273 0.295 0.302 (0.890)

Exon 1c promoter CON 0.193 184 87 11 0.967

rs3782221 8365390 SCD 0.449 83 146 54 0.569 0.887 0.891 (1.000)

Intron 1 CON 0.453 82 149 55 0.472

rs3782219 8357749 SCD 0.415 95 142 47 0.732 0.967 0.968 (1.000)

Intron 1 CON 0.414 90 155 41 0.068

rs561712 8321578 SCD 0.193 184 89 10 1.000 0.748 0.753 (1.000)

Intron 3 CON 0.200 179 98 8 0.294

rs3782206 8314598 SCD 0.217 172 101 11 0.552 0.596 0.591 (0.996)

Intron 3 CON 0.230 174 91 20 0.133

rs6490121 8277704 SCD 0.414 93 147 44 0.328 0.651 0.654 (0.999)

Intron 10 CON 0.427 96 137 54 0.747

rs2682826h 8222347 SCD 0.324 132 120 32 0.621 0.0007 0.0005 (0.0031)

Exon 29 CON 0.423 97 136 53 0.728

Male SCD 0.319 90 83 20 0.991 0.0003 0.0002 (0.0013)

Male CON 0.449 55 94 36 0.856

Female SCD 0.335 42 37 12 0.509 0.425 0.402 (0.959)

Female CON 0.376 42 42 17 0.324

a SNPs identification number and position are determined by NCBI dSNP (http://www.ncbi.nlm.nih.gov/sites/entrez?d=snp).b SCD suicide, CONcontrol.c MAFminor allele frequency.d

M major allele, m minor allele.e HWEHardyWeinberg equilibrium.f Genotypic p values were tested with CochranArmitage test for trend.g This column shows nominal p values and corrected p values for multiple testing (in parentheses).h Boldface represents significant differences between the completed suicides and controls in males, but not in females.

Table 2Genotype and allele frequency of the rs2682826 SNP among the suicides with violent methods.

SNP Phenotypea MAFb Genotype distributionc p value

M/M M/m m/m HWEd Genotypee Allelef

rs2682826 Total SCD 0.325 101 95 24 0.904 0.007 0.0066 (0.0339)

Total CON 0.413 77 109 38 1.000

Male SCD 0.341 67 73 17 0.831 0.0345 0.037 (0.1884)

Male CON 0.421 52 80 27 0.844

Female SCD 0.286 34 22 7 0.362 0.0878 0.0718 (0.3562)

Female CON 0.392 25 29 11 0.745

a SCD suicide, CONcontrol.b MAFminor allele frequency.c Mmajor allele, m minor allele.d HWEHardyWeinberg equilibrium.e Genotypic p values were tested with CochranArmitage test for trend.f

This column shows nominal p values and corrected p values for multiple testing (in parentheses).

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Our finding that the rs2682826 SNP is associated with suicidal

behavior especially in males implies that this SNP may affect the neural

NO pathways differently in males and females. Because the worldwide

rateof suicide is3.5 timeshigherin malesthan in females (WHO, 2005),

thebiological mechanisms of suicidal behavior maybe differentin males

and females. The expression and regulation of the NOS1 gene were

suggested to be different in males and females (Ishihara et al., 2002).

Male mice lacking NOS1 exhibit impulsive aggression with decreased

serotonin turnover in the brain regions regulating emotion (Nelsonet al., 1995; Demas et al., 1999; Chiavegatto et al., 2001). Therefore, sex

hormones might influence the NOS1 activity, and may confound the

effectof rs2682826SNP on neuralNO pathways in females. Importantly,

clinical approaches have shown that impulsivity and aggression are the

strongest emotional traits to be associated with both males and suicidal

behavior (Turecki, 2005; Mann et al., 2009). Thus, our finding of

significant association of the rs2682826 with suicide in males seems

consistent with these animal and human studies and raises a possibility

that NOS1-mediated impulsive aggression may contribute to an

increased suicide risk, especially in males.

One limitation forour present study is a lack of clinical background

for suicide victims due to our ethical code for genetic studies. Higher

incidence of suicidal behavior has been consistently observed in

several psychiatric disorders including major depression, bipolar

disorder, and schizophrenia. We cannot formally exclude a possible

association of rs2682826 SNP with those psychiatric disorders rather

than suicide itself. However, it should also be noted that despite the

highest risk of suicide in psychiatric disorders, most patients never

attempt suicide, suggesting that pathways involved in suicidal

behavior might be independent from main psychiatric disorders

(Mann, 1998, 2003; Rujescu et al, 2007; Ernst et al, 2009 ). Indeed,

considerable genetic association studies did not show any significant

associations of NOS1 gene polymorphisms with major depression and

bipolar disorder (Okumura et al, 2010; Yu et al, 2003; Fallin et al.,

2005; Buttenschon et al., 2003), two main psychiatric disorders with

highest suicide risk. Thus, we would predict that the significant

association of rs2682826 with suicide in the present study may not be

attributable to other psychiatric disorders.

The second limitation of our study is that the selected SNPs are notrigorously based on criteria for the tag SNP selection for the whole

gene locus. We selected the SNPs based on the previous reports which

suggested being associated with several psychiatric diseases. There-

fore the SNPs selection might bias our results. In addition, a sample

size for this study is not enough to conclude the association between

the NOS1 gene and suicide. We cannot fully exclude the possibility of

type I error for the association of the rs2682826 SNP with suicide, and

thepossibilityof type II error for thelack of association of the other six

SNPs with suicide as well.

In conclusion, our study provides evidence to support the possible

involvement of NOS1 gene polymorphism in suicidal behavior,

especially in male. This involvement might be partly explained by

the NOS-1 mediated impulsive aggression although this biological

mechanism needs to be further clarified. The minor T allele ofrs2682826SNP may have a protective role against suicidal behavior in

males. Further studies with a large sample size are needed to confirm

our finding in independent groups.

Acknowledgment

This work was supported in part by research grants from the

Ministry of Education, Culture, Sports, Science and Technology in

Japan.

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A common polymorphism in the 3′-UTR of the NOS1 gene was associated with completed suicides in Japanese male population