Molecular Psychiatry (2004) 9, 197–202 & 2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE A meta-analysis of the association between the gene polymorphism (5-HTTLPR) and trait anxiety JA Schinka1,2, RM Busch1,3 and N Robichaux-Keene1,4 1Veteran’s Administration Medical Center, Tampa, FL, USA; 2Department of Psychiatry, University of South Florida, Tampa, FL, USA; 3Department of Psychology, University of Cincinnati, Cincinnati, OH, USA; 4Department of Psychology, Baylor University, Waco, TX, USA

Studies of the association between polymorphisms of the serotonin transporter gene (5-HTT) and trait anxiety have produced inconsistent results, raising questions about the strength of the relationship and the methodological conditions under which the relationship holds. We conducted a meta-analysis of existing studies to provide formal statistical measures of the strength of the linked polymorphic region of the serotonin transporter gene (5-HTTLPR)– anxiety relationship. For the entire collection of 26 studies, results provided no support for a relationship between anxiety and the presence of the short form of the 5-HTTLPR polymorphism. There was strong evidence of the presence of moderating variables, however, and subsequent analysis revealed that choice of the measure of trait anxiety was significant. Studies using the scale of Costa and McCrae were found to produce a small positive effect (d¼0.23). Other potential moderators (country of study origin, type of subject) did not have a meaningful impact on d statistics. These findings indicate that 5-HTTLPR may in fact have a small but reliable influence on personality, particularly in the manifestation of trait anxiety when measured with a neuroticism scale based on the five-factor model of personality. Our results suggest that the success of future personality genetics research will be maximized by the use of personality measures from both the psychobiological and five-factor models. Molecular Psychiatry (2004) 9, 197–202. doi:10.1038/sj.mp.4001405 Keywords: personality; genetics; questionnaire; association study; serotonin; meta-analysis

Introduction numerous 5-HTT-anxiety studies have been reported, with most examining the LPR polymorphism. These Twin studies have consistently demonstrated that studies have produced a large set of both positive and individual differences in reliably measured dimen- negative results and have generated extensive com- sions of personality are substantially influenced by ment about the strength of the relationship and genetic factors.1,2 Only in the past few years, however, the methodological conditions under which the have specific genetic polymorphisms been identified relationship hold.5–8 To date, however, no formal as factors influencing specific personality traits. In statistical analysis has addressed the collection of 1996, Lesch et al3 examined the relationship between studies examining the relationship between 5- the linked polymorphic region of the human seroto- HTTLPR and trait anxiety. In this study, we con- nin transporter gene (5-HTTLPR) and anxiety-related ducted meta-analyses of existing studies to provide traits (which we will refer to throughout as trait formal statistical measures of the strength of this anxiety) in a sample of healthy American volunteers. relationship. They found a small (d¼0.28) but significant relation- ship between Neuroticism, a measure of trait anxiety 4 contained in the revised NEO Personality Inventory, Methods and 5-HTTLPR. Specifically, individuals with the short form of 5-HTTLPR (s/s or s/l) had higher scores Studies on Neuroticism than individuals with the homozy- We conducted a search for all available studies of the gous long form (l/l). Since this original finding, association between 5-HTTLPR and measures of anxiety in adults by examining journal abstracts available through March 1, 2003 in the following Correspondence: JA Schinka, PhD, VA Medical Center/116B, databases: PubMed at the National Library of Medi- 13000 Downs Blvd, Tampa, FL 33612, USA. E-mail: [email protected] cine, PsycInfo, Science Direct, and MedLine. The Received 07 April 2003; revised 23 May 2003; accepted 12 June search identified 33 studies, seven of which were 2003 excluded from the analysis. We excluded one study9 5-HTTLPR and anxiety JA Schinka et al 198 because the same data are analyzed in two earlier ‘anxiety factor’ score by averaging scores across the reports5,10 that are included in the meta-analysis. We scales. excluded three studies11–13 because they examined allele and/or genotype frequencies among individuals Results scoring at high and low levels on an anxiety measure, rather than testing differences in trait anxiety scores Table 1 presents descriptive information and effect between genotype groups. One study14 was not sizes for 28 samples described in 26 separate studies, included because sufficient descriptive data were comprising 7657 subjects, which examined the not provided to allow independent calculation of relationship between anxiety and the presence/ effect sizes. Finally, we excluded two studies15,16 absence of the short genotype. The range of d values because they did not provide clearcut or well-studied across samples and studies is quite substantial (À0.31 measures of anxiety-related traits. The meta-analysis to 0.58). Eight (29%) of the d values are negative in was therefore conducted on results provided in 26 direction and the majority (19 of 28, 68%) are less published studies.3,5,6,10,17–38 As one study presented than 0.2. data for multiple samples, 28 samples were available Table 2 presents the results of the meta-analysis for for analysis. the entire collection of studies. The mean difference Each article was coded according to the following: in measured anxiety between short and long groups is (1) reference, (2) scale or test used as a measure of an negligible (d¼0.10, 1/10 of a standard deviation). The anxiety-related trait, (3) type of subject (normal vs. confidence interval for the mean includes zero, patient), (4) country of sample origin, (5) sample size indicating that the mean effect is not significantly by genotype, (6) mean scores for the trait anxiety different from zero. However, the set of d values is measure by genotype, and (7) standard deviation of characterized by a substantially large standard devia- scores by genotype. tion (0.18) and a relatively small estimate for

Although providing data on only a single sample, sampling error (Vare¼0.001). According to the Hunter several studies used more than one measure of trait and Schmidt method, the ratio of sampling error

anxiety. In all, 13 studies used the harm avoidance variance to the variance of d (Vare/Vard) provides an (HA) scale of either the Tridimensional Personality estimate of the variability in results across studies Questionaire40 (TPQ) or the Temperament and Char- that can be attributed to sampling error. For the entire acter Inventory41 (TCI) as a measure of trait anxiety, collection of studies, only approximately 2% of the while 11 studies used the Neuroticism (N) scale of the variability in results across studies can be attributed revised NEO Personality Inventory (NEO-PI-R). Three to sampling error. In addition, a formal test of the studies used the Neuroticism scale of either the assumption of homogeneity produced a significant Eysenck Personality Questionnaire42 or the Eysenck result (Q¼171.92, df¼27, Po0.001), indicating het- Personality Inventory.43 Two studies21,32 provided erogeneity in the distribution of d values. These data for all of the anxiety scales of the Karolinska results argue strongly for the presence of unknown Personality Inventory.44 moderators of the association between 5-HTTLPR and The meta-analysis was conducted on effect sizes trait anxiety. and the method of analysis was guided by the work of Given the statistical evidence for the presence of Hunter and Schmidt.45 Effect size (d) was calculated moderators, we calculated additional d values for four as the difference in anxiety measure means between possible factors: studies with extreme d values, the groups (ie, s/s and s/l vs l/l genotypes) divided by the country of origin of the samples, type of subject pooled standard deviation of the two groups. All ds (normal vs patient), and the measure of trait anxiety. were calculated so that a higher mean for the Examination of summary statistics in Table 2 suggests combined s/s and s/l (short) group was reflected in a that the results are only minimally influenced positive value for d.Ad of 1 thus means that the short materially by studies with the most extreme d values group had a mean that was one standard deviation (À0.31 and 0.58), as the d statistic changes little by higher than for the l/l (long) group. A d of zero would exclusion of those studies. The d statistic for the 13 indicate that there was no difference in means studies conducted with samples from the USA does between the short and long groups. By convention, increase over that for all studies, but the confidence ds of |0.2|, |0.5|, and |0.8| are considered to be interval continues to include zero, indicating that the indications of small, medium, and large effect sizes, mean effect is not significantly different from zero. respectively.46 Exclusion of studies using patient subjects, leaving Several studies did not provide means and standard only studies of normal adults, also has little impact on deviations for the short and long groups, but did the d statistics, as might be expected from the fact that provide correlation coefficients or the results of t or F over 80% of the subjects were from normal samples. tests. In these cases, d was calculated from r, t,orF, The moderator analyses do indicate a substantial using standard formulas.45 For studies reporting the and significant effect, however, for the choice of results of more than one measure of trait anxiety, we anxiety measure. The 13 studies using the HA scale calculated an average effect size across measures. produce a mean d of 0.04, lower than that for the For studies using several anxiety scales from the entire collection of studies. In contrast, the 11 studies Karolinska Personality Inventory, we computed an using the N scale of the NEO-PI-R produce a mean d

Molecular Psychiatry 5-HTTLPR and anxiety JA Schinka et al 199 Table 1 Sample descriptions and d values for studies of the influence of 5-HTTLPR on trait anxiety

Study Test Scale Sample N Country d

Lesch et al (1996) NEO N Normal 505 USA 0.28 Ebstein et al (1997) TPQ HA Normal 121 Israel À0.07 Gelertner et al (1998) TPQ/ HA/ Personality disorders 322 USA 0.07a NEO Na substance abusers/normal Jorm et al (1998) EPQ N Normal 759 Australia 0.01 Mazzanti et al (1998) TPQ HA Criminal and normal 397 Finland 0.06 Ricketts et al (1998) TPQ HA Parkinson’s and normal 84 USA 0.58 Flory et al (1999) NEO N Normal 225 USA 0.00 Gustavsson et al (1999) KSP Anx Normal 300 Sweden À0.08 Hamer et al (1999) TCI HA Normal 634 USA 0.20 Katsuragi et al (1999) TPQ HA Normal 101 Japan À0.14 Kumakiri et al (1999) TCI/ HA/ Normal 144 Japan 0.05a NEO Na Benjamin et al (2000) TPQ HA Normal 454 Israel À0.13 Du et al (2000) NEO N Normal 186 Canada 0.02 Greenberg et al (2000) NEO N Normal 397 USA 0.31 Herbst et al (2000) TCI HA Normal 425 USA À0.13 Hu et al (2000) NEO N Normal 759 USA 0.31 Lerman et al (2000) EPI N Normal 185 USA 0.02 Osher et al (2000) TPQ/ HA/ Normal 148 Israel 0.35a NEO Na Schmidt et al (2000) NEO N Normal 72 USA 0.39 Golimbet et al (2001) EPI N Affective patients 114 Russia 0.06 EPI N Patient’s relatives 87 Russia À0.09 EPI N Normal 156 Russia À0.09 Jang et al (2001) NEO N Normal 388 USA 0.30 Melke et al (2001) KSP Anx Normal 191 Sweden 0.04 Samochowiec et al (2001) TCI HA Normal 126 Poland À0.31 Cohen et al (2002) TPQ HA Fibromyalgia patients 99 Israel 0.20 Stoltenberg et al (2002) FFI N Alcoholics and normal 86 USA 0.01 Tsai et al (2002) TPQ HA Normal 192 China 0.03

Note. TPQ¼Tridimensional Personality Questionnaire, TCI¼Temperament and Character Inventory, KSP¼Karolinska Scales of Personality, EPI¼Eysenck Personality Inventory, EPQ¼Eysenck Personality Questionnaire, N¼neuroticism, HA¼harm avoidance.aEffect sizes are averaged across the HA and N scales, as data are taken from the same sample.

Table 2 Summary of meta-analysis of association between 5-HTTLPR and measures of trait anxiety

d

Description Number of Number of Total

studies samples N M SD Vard Vare 95% CI

All studies 26 28 7657 0.10 0.18 0.031 0.001 À0.24 to 0.44 Without extremes 24 26 7447 0.10 0.15 0.022 0.001 À0.19 to 0.40 USA studies 13 13 4382 0.18 0.18 0.029 0.001 À0.16 to 0.51 Normal subjects only 20 21 6370 0.10 0.18 0.033 0.001 À0.26 to 0.46 HA studies 13 13 3247 0.04 0.17 0.033 0.001 À0.32 to 0.39 HA studies, normals only 9 9 2345 0.01 0.18 0.033 0.002 À0.35 to 0.37 N studies 11 11 3091 0.23 0.11 0.015 0.001 0.02 to 0.45 N studies, normals only 9 9 2820 0.25 0.11 0.012 0.001 0.03 to 0.46

Note.Vard¼variance of d,Vare¼variance due to sampling error, N¼neuroticism, HA¼harm avoidance. of 0.23. Although this is a small effect, examination of sampling error to just over 8%. As sampling error the confidence interval reveals that it is significantly accounts for such a small percentage of variance in d different from zero. Even consideration of this values, it is highly likely that other unknown factors moderator, however, increases the proportionate also moderate the association between 5-HTTLPR and amount of variance in d values attributable to trait anxiety.

Molecular Psychiatry 5-HTTLPR and anxiety JA Schinka et al 200 To explore the effect of choice of anxiety measure individual differences in underlying trait anxiety. further, we examined whether the difference in d Some explication of the unshared variance can be values for studies using HA vs N measures could be found by looking at the intercorrelations of the scales explained by other differences in sample character- for the TPQ/TCI and the NEO PI-R. In two studies,48,49 istics. Consideration of studies conducted only in the HA has been found to have a substantially high USA did not substantially increase the d value for negative correlation (À0.32 to À0.52) with NEO-PI-R studies using either scale as a measure of anxiety. Extraversion. This appears to be due in large part to Similarly, there was no appreciable change in d the substantial correlation (À0.45) between the HA values when studies using only normal subjects were subscale of Shyness and Extraversion.49 Both scales used. have substantial cross-correlations with other scales in the same model. The angry hostility subscale of N 4 Discussion correlates negatively with agreeableness (r¼À0.48), while the uncertainty subscale of HA correlates Genotypes of 5-HTTLPR have been the most fre- negatively with (r¼À0.49).50 quently studied cases in the investigation of the Studies examining correlations of the HA and N genetics of trait anxiety. Our meta-analysis of 26 scales with other self-report measures of trait anxiety studies involving 7657 subjects suggests that there is also reveal a pattern of differential relationships. The no clearcut, meaningful association between N scale correlates highly51 (r¼0.77) with Eysenck’s 5-HTTLPR genotypes and anxiety. The calculated Neuroticism scale; the HA scale correlates at a lower effect size was 0.10, approximately 1/2 of the effect level52 (r¼0.30), a finding in keeping with the fact that typically considered to be a small effect. Examination the item content of the Eysenck scale more closely of potential moderating variables showed that exclu- parallels that of the scales of N than of HA. In sion of studies with extreme d values did not affect summary, the differences in mean d values obtained overall d. While restriction of studies to those with for the two scales likely reflects the fact that the two samples from the USA did increase d to 0.18, the scales measure the construct of trait anxiety in effect size continued to be below that considered to be different ways—in brief, the two scales measure a small effect. No change in d was found when the somewhat different constructs. analyses were restricted to normal subjects. It is widely recognized that the genetic structure of The moderator analysis did reveal, however, that personality is complex and polygenic in nature, with choice of anxiety measurement scale was a significant several genes contributing in small ways to individual moderator. In contrast to the d of 0.04 that was differences in specific personality dimensions. obtained for studies employing the HA scale, studies Although the association between 5-HTTLPR and using the N scale produced a d of 0.23. This trait anxiety is small, our results suggest that they are difference in d values could not be explained by real, at least under the condition that they are differences in subject characteristics or country of measured by an FFM neuroticism scale. Further origin of the studies using these two scales as a examination of the influence of 5-HTTLPR, in inter- measure of anxiety. Although it may be surprising action with other candidate genes, on personality that choice of measurement scale would be a potent offers some element of promise. Our results suggest moderator of the 5-HTTLPR–anxiety relationship, that the success of future personality genetics re- there is ample theoretical and empirical evidence to search will be maximized by the use of personality support such a hypothesis. The HA scale is formed by measures from both the psychobiological and FFMs. four subscales that address different facets of anxiety As each of the models parses the elements of in Cloninger’s psychobiological model: worry, fear of personality in a different way, it is certainly possible uncertainty, shyness, and fatigability. The N scale that other patterns of gene–trait relationships may be measures one of the five major domains in the lexical uncovered that are unique to one of the models of five-factor model (FFM):47 neuroticism, extraversion, personality. 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