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An Association Study of a Functional Polymorphism of the Serotonin Molecular Psychiatry (1998) 3, 449–451 1998 Stockton Press All rights reserved 1359–4184/98 $12.00 ORIGINAL RESEARCH ARTICLE cal power. Here we report data from a population sam- ple of 759 Caucasians which is larger than any study so far. The study includes measures of anxiety-related An association study of a personality traits (neuroticism, negative affect, behavioral inhibition), anxiety and depressive symp- functional polymorphism of toms, and a measure of alcohol misuse. The allele frequencies were 56.5% for the long allele the serotonin transporter and 43.5% for the short. The genotype frequencies gene with personality and were: long/long 33.5%, long/short 46.1%, and short/short 20.4%. psychiatric symptoms Table 1 shows the mean scores on the personality and psychiatric symptom measures. For most scales, AF Jorm1, AS Henderson1, PA Jacomb1, the numbers of subjects were slightly smaller than H Christensen1, AE Korten1, B Rodgers1, indicated in the table because of missing data. There X Tan2 and S Easteal2 were no significant differences at the P Ͻ 0.05 level on any measure when the data were analyzed by geno- 1NHMRC Psychiatric Epidemiology Research Centre, The type. Similarly, there were no significant differences Australian National University, Canberra 0200; 2John when short/short and long/short individuals were Curtin School of Medical Research, Australian National combined into one group and contrasted with the University, Canberra 0200, Australia long/long group. There were also no significant differ- ences between genotypes in age, sex, education or occupational status, so it was not necessary to adjust Keywords: neuroticism; extraversion; psychoticism; anxiety; for these as covariates in the analysis. depression; alcohol abuse; genetics; serotonin transport A check was also made for interaction effects involv- A functional polymorphism in the regulatory region of ing the alleles and environmental risk factors (adverse the serotonin transporter gene has been reported to be life events and childhood experiences), but the results associated with anxiety-related personality traits.1 We were also negative. attempted to replicate this finding in an association This study found no associations of the 5-HTTLPR study involving 759 Caucasians selected from the gen- polymorphism with anxiety-related personality traits eral Australian population. We found no associations or with anxiety or depressive symptoms. These find- with personality traits (including neuroticism, negative ings are inconsistent with those reported by Lesch et affect and behavioral inhibition), anxiety and depressive al,1 but consistent with subsequent negative studies.2– symptoms, or alcohol misuse. 4 Given that our sample size is larger than that of Lesch The human serotonin transporter (5-HTT) gene has et al and of the negative studies, lack of statistical a functional polymorphism in its regulatory region power is not a likely explanation. The present sample which Lesch et al1 found to be associated with anxiety- size has nearly 80% power to detect associations related personality traits. Individuals with a short accounting for 1% of the variance. If the 5-HTTLPR allele in the 5-HTT gene-linked polymorphic region (5- polymorphism is associated with anxiety-related traits, HTTLPR) scored higher on neuroticism, anxiety and the effect must be very small. harm avoidance than those who were homozygous for The study also adds to the negative data on associ- the long allele. The association was found in both ations of the 5-HTTLPR polymorphism with other per- population and sib-pair samples which were predomi- sonality traits.1,3–4 We found no associations with the nantly Caucasian. Extraversion and Psychoticism scales of the Eysenck Subsequent studies have not been able to replicate Personality Questionnaire, nor with the Fun Seeking, these results. Several studies have failed to find associ- Reward Responsiveness and Drive scales of the ations of the 5-HTTLPR with neuroticism and harm BIS/BAS. The latter measures are based on Gray’s con- 2–4 avoidance. Association studies with psychiatric dis- cepts of personality,13 but bear a close resemblance to orders have also generally been negative, including Cloninger’s concepts which have been previously 5–7 studies on panic disorder, unipolar and bipolar examined in association studies.14 8 9 affective disorder and anorexia. However, a study of The present study also found no association with unipolar and bipolar affective disorder in three centres scores on a screening test for alcohol use disorders. did find an association with the short allele in the com- Although a previous study did report an association of bined data from the centres, even though the associ- the 5-HTTLPR polymorphism with alcohol depen- ations were not statistically significant in the individ- dence, this was with a sample of severely affected ual centres.10 Associations have also been reported alcoholics with a history of withdrawal seizure or between the short allele of the 5-HTTLPR and severe delirium.11 Such individuals are likely to be rare in the alcohol dependence11 and late-onset Alzheimer’s dis- general population sample reported on here. ease.12 In a community survey such as this, it is possible A limitation of the negative studies is that their sam- that those who refused to participate differed on the ple size is smaller than the original study of Lesch et personality trait of neuroticism or on anxiety and al,1 which leaves open the possibility of lack of statisti- depressive symptoms. Unfortunately, the only data we A functional polymorphism of the serotonin transporter gene AF Jorm et al 450 Table 1 Mean scores (and standard deviations) on personality and psychiatric symptom scales according to 5-HTT regulatory region genotype Scale Genotype Long/long Long/short Short/short (n = 254) (n = 350) (n = 155) EPQ-R Neuroticism 4.42 (3.33) 4.49 (3.27) 4.36 (3.50) Extraversion 7.12 (3.39) 7.15 (3.57) 7.52 (3.35) Psychoticism 1.99 (1.62) 2.19 (1.60) 1.89 (1.60) PANAS Negative affect 9.07 (3.70) 9.10 (3.67) 9.23 (4.30) Positive affect 17.32 (3.21) 17.47 (3.30) 17.50 (2.99) BIS/BAS BIS 20.85 (3.47) 20.44 (3.56) 20.85 (3.52) BAS reward 16.70 (2.30) 16.58 (2.05) 16.50 (2.11) BAS drive 10.07 (2.67) 10.06 (2.59) 10.10 (2.44) BAS fun 11.00 (2.32) 10.85 (2.55) 11.02 (2.43) DSSI Anxiety 2.81 (2.93) 2.80 (2.74) 2.94 (2.91) Depression 1.77 (3.00) 1.70 (2.58) 1.65 (2.55) Goldberg scales Anxiety 3.58 (2.80) 3.65 (2.67) 3.40 (2.74) Depression 2.44 (2.40) 2.39 (2.19) 2.23 (2.27) AUDIT 5.08 (4.40) 4.75 (3.70) 5.16 (4.35) Note: EPQ-R = Eysenck Personality Questionnaire—Revised; PANAS = Positive and Negative Affect Schedule; BIS/BAS = Behavioral Inhibition System/Behavioral Activation System; DSSI = Delusions-Symptoms-States Inventory; AUDIT = Alcohol Use Disorders Identification Test. have on the refusers is age and sex, with the young Methods more likely to refuse and the middle-aged less likely. Sample However, results from a longitudinal study of a British Participants were recruited from the Electoral Roll for birth cohort suggest that neuroticism is unrelated to Canberra, Australia. Enrolment to vote is compulsory participation, while having a psychiatric disorder pre- for all Australian citizens aged 18 or over. Interviews 15 dicted a slightly higher participation rate. were completed with 2725 individuals, representing a The frequency of short alleles in the present study response rate of 67% from those who were contactable. was very close to that reported by Lesch et al (43.5% vs The data reported here are from a representative sub- 1 43%) in a predominantly Caucasian sample, but much sample of 759 Caucasian individuals who were geno- lower than the frequency in Japanese samples (77% typed for 5-HTTLPR. Race was ascertained by asking 4,6 and 83.3%), and slightly lower than an Israeli sample participants ‘How would you describe your racial 3 (53%). There appear to be major ethnic differences group?’ and providing the options: Caucasian/White, which are a potential confounding factor in association Asian and Other. In the total sample, 95% described studies of the 5-HTTLPR. Although we only included themselves as Caucasian/White, 3.2% as Asian and individuals who described themselves as 1.8% as Other. ‘Caucasian/White’, it is possible that some might have had some non-Caucasian ancestry. However, this prob- Questionnaire lem is likely to be small because only 5% of the popu- Participants were asked to complete a questionnaire lation described themselves as other than Caucasian which covered socio-demographic characteristics, per- and the opportunity for racial admixture is conse- sonality, anxiety and depression symptoms, alcohol quently reduced. Furthermore, Australians of mixed abuse, life events, social support and childhood experi- race (eg Aboriginal Australians) tend not to describe ences. This was done under the supervision of a pro- themselves as Caucasian even in cases where they have fessional interviewer. The participants were also asked predominantly Caucasian ancestry. to provide a cheek swab from which DNA could be The findings of Lesch et al1 were very exciting and extracted. The following components of the question- suggested a new direction for investigating genetic fac- naire are relevant to the present paper: the Behavioral tors in psychiatric disorders. While their findings have Inhibition System/Behavioral Activation System not been replicated, the approach they have taken of (BIS/BAS) scales;13 the Extraversion, Neuroticism and investigating a functional polymorphism in relation to Psychoticism scales of the short form of the Eysenck a vulnerability trait retains its appeal.
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