Molecular Psychiatry (2003) 8, 840–852 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp FEATURE ARTICLE Genetics of personality: are we making progress? S Van Gestel1 and C Van Broeckhoven1 1Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB8), University of Antwerp (UIA), Antwerpen, Belgium

For centuries, scientists are intrigued by the differences in personality between individuals. As early as in the ancient Greek civilization, people tried to formulate theories to systematize this diversity. With the increased interest in behavior genetics, personality was also considered a challenging phenotype. From the early start, studies suggested a heritable component in personality. After the successes of molecular genetic studies in unraveling the genetic basis of (mostly) monogenic diseases, the focus shifted towards complex traits, including psychiatric disorders. It was observed in several studies that personality measures differed between patients with psychiatric disorders and healthy controls. Therefore, normal personality was considered a viable endophenotype in the search for genes involved in psychiatric disorders such as affective disorders, ADHD and substance dependence. Genes that were to be found in studies on personality could be candidate genes for particular psychiatric disorders. In the course of time, however the study of genes for personality turned out to be at least as hard as the search for genes involved in other complex disorders. In this review, past studies, present problems and future directions concerning the study of personality genetics are discussed. Molecular Psychiatry (2003) 8, 840–852. doi:10.1038/sj.mp.4001367 Keywords: personality; temperament; character; genetics; candidate genes; polymorphisms; susceptibility

Different people have different personalities. Over of personality, building upon existing literature time, multiple theories and concepts of personality concerning personality and temperament. The initial have been formulated.1–4 The so-called trait psychol- model defined personality as consisting of three ogists conceptualize personality as encompassing temperament traits: (NS), harm different traits. Eysenck5 postulated the existence of avoidance (HA) and (RD).10 Later, the following three traits: , extraversion a fourth temperament dimension, persistence (P), and and , which can be measured with the three character traitsFself-directedness (SD), coop- Eysenck Personality Questionnaire (EPQ).6 Cattell et erativeness (C) and self-transcendence (ST)Fwere al7 used a lexical approach by looking for clusters of included.11 Temperament traits refer to basic emo- traits in the adjectives people use to describe an tional response patterns and are assumed to be individual’s personality and found 16 factors, which heritable and manifesting early in life. Character can be measured by the Sixteen Personality Factor traits are hypothesized to be voluntary goals and Questionnaire (16PF). Using the same method, sev- values, acquired during development and influenced eral researchers reached consensus on a model with by sociocultural learning. In the biological part of the five traits. Different descriptions of these five traits model, the authors postulated that NS is influenced exist,8 but the most widely used terminology was set by dopamines, that HA is related to the serotonin by Costa and McCrae,9 who designated them as system and that RD is under the influence of the neuroticism, extraversion, , open- noradrenergic system.10 The Tridimensional Person- ness and . A questionnaire designed to ality Questionnaire (TPQ)12 is a self-report question- measure these big 5 is the NEO Personality Inventory naire designed to measure the original three (NEO-PI) and its derivatives, such as the NEO-PI-R temperament dimensions. Later, the Temperament and NEO-FFI.9 and Character Inventory (TCI)13 was constructed to In a somewhat different line of research, Cloninger measure the seven dimensions from the complete and colleagues developed the psychobiological model psychobiological model. Adoption, twin and family studies have demon- strated the importance of genetic influences on Correspondence: Professor Dr Christine Van Broeckhoven, PhD, personality. In an early study using 137 young twin DSc, Department of Molecular Genetics, Neurogenetics Group, pairs, the parents rated personality. The average University of Antwerp (UIA), Universiteitsplein 1, B-2610 correlation of 11 personality scales was 0.55 for Antwerpen, Belgium. E-mail: [email protected] Received 7 February 2003; revised 11 April 2003; accepted 16 monozygotic (MZ) and À0.07 for dizygotic (DZ) April 2003 twins.14 The fact that the DZ correlation was less Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 841 than half of the MZ correlation was later explained by genes from these three specific neurotransmitter referring to contrast effects, by which parents tend to pathways. exaggerate the differences between DZ twins.15 Most of the studies on personality did not rely on parent ratings, but on data from self-report questionnaires. In The first and most frequently examined polymorph- a large study on personality and social attitudes ism until now in personality studies is the 48-bp including more than 14 000 twins and their relatives, VNTR in exon 3 of the dopamine D4 receptor gene both additive and dominant genetic effects were (DRD4).21 The first reports of a possible association of observed.16 The effect of the family environment, this particular polymorphism with the trait of NS including vertical cultural transmission was much were published in 1996. Two groups reported a less marked. The same picture emerged from a review positive association of the 7-repeat allele of the 48- of the genetics of personality, in which the authors bp VNTR with NS. One study included 124 Jewish stated that there is a substantial genetic contribution healthy volunteers22 and used TPQ to measure to individual differences in personality as measured personality. The other study23 examined American by self-report questionnaires.17 The heritability esti- Caucasian volunteers, in which personality was mates ranged between 0.40 and 0.60, of which part assessed by the NEO-PI-R. TPQ NS scores were was nonadditive. Furthermore, they stated that there estimated from the scores calculated with the NEO- is no contribution of shared environment, but that a PI-R inventory. Both studies detected an association large part of the variance is attributable to nonshared of the 7-repeat allele with high NS, of which the effect environment and measurement error. accounted for 3–4% of the total variance. Some In family studies, the heritability estimates for studies replicated the association,24–28 while in others personality traits reached 0.30,17,18 which is some- no effect could be demonstrated, neither in healthy what lower than the estimates from twin studies. A individuals29–43 nor in patient populations.30,44–48 In a possible explanation for this difference in heritability linkage study using families of alcoholics, the estimates depending on the study design could be dimension of HA and not NS was linked to DRD4.49 nonadditive genetic factors that play a role in Some studies showed association between DRD4 personality. A nonadditive genetic effect such as and NS in the opposite direction. In a study using dominance can only be measured in sibs sharing extremely high and low scoring groups of individuals, two alleles identical by descent (IBD) at a certain the 2- and 5-repeat alleles, and not the 7-repeat allele, locus, being all MZ twins and 25% of the DZ twins were more frequent in the group of high NS and ordinary sib pairs. Therefore, in twin studies the individuals.50 In two other studies, lower NS was chances of detecting the dominance genetic compo- associated with the 7-repeat allele: one was a study in nent are higher than in family studies. Another a group of alcoholic offenders,29 the other in a group explanation might be found in one of the basic of substance-dependent African Americans.30 assumptions made in twin studies, known as ‘equal Not only in adults, but also in newborns, the environments’, in which it is stated that shared association between DRD4 and NS was tested. A environments of MZ and DZ twins are not different.19 group of neonates was tested at 2 weeks, 2 and 12 If, however, MZ twins were treated more alike than months of age, and associations between DRD4 and DZ twins because of their greater similarity, this different measures of activity and NS were ob- would result in an overestimation of the heritability. served.51–53 A combined effect of the DRD4 48-bp However, in a study by Plomin et al,20 it was noted VNTR and a polymorphism in the serotonin trans- that the greater resemblance in appearance of MZ porter gene (5-HTT) was reported on infants’ response compared to DZ twins did not result in more similar to novelty at 12 months of age.54 In two recent meta- personality scores, as rated by the mother of the analyses, the association between the DRD4 VNTR twins. To the contrary, the evidence even pointed in polymorphism and NS could not be confirmed.55,56 the direction of contrast effects, which would lead to Table 1 overviews the studies on the DRD4 VNTR and an underestimation of the heritability. NS with details on the study design. Other studies investigated the association of NS with a single nucleotide polymorphism (SNP) at Molecular genetics of personality position À521 in the promoter region of DRD4. Again, Candidate gene studies some observed an association,57,58 while others did A frequently used design in molecular genetic studies not.40,42,43,59 A meta-analysis supported the associa- of personality is the candidate gene approach. Since tion between NS and the –521 C/T polymorphism.56 processes in brain were assumed to regulate person- The DRD4 polymorphisms were also studied in ality, genes involved in neurotransmitter pathways relation to the trait of extraversion. No associations were primary candidates. In the psychobiological were found using the VNTR polymorphism60 or the model of personality, three temperament dimensions –521 promoter SNP.61 were hypothesized to be linked to one of three Interestingly, in a recent study on female Korean neurotransmitter systems: NS to dopamine, HA to adolescents, a combined effect of the 48-bp VNTR and serotonin and RD to noradrenaline.10 These theore- the –521 C/T polymorphism was detected on NS and tical assumptions led several researchers to examine P, while no single associations with either of the

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 842 Table 1 Overview of studies testing the association between the 48-bp repeat polymorphism in DRD4 and NS

Inventory a Country Participants Population % Males Ref.

KSP Sweden 126 Healthy individuals 60 31 NEO-FFI Germany 115 Healthy volunteers 25 43 NEO-PI-R USA 315 Volunteers 95 23b NEO-PI-R USA 200 Elderly individuals 56 32 TCI Austria 109 Healthy individuals 28 36 TCI Finland 190 Extreme scoring intable Adividuals 50 50b TCI Japan 153 Healthy students 0 25b TCI Japan 69 Healthy individuals 0 27b TCI Japan 173 Personnel self-defense forces 100 39 TCI Korea 101 Adolescent volunteers 0 62 TCI New Zealand 86+181 Depressives+individuals from alcoholism pedigrees 40 45 TCI Sweden 381 General population 55 40 TCI Sweden 109+113 Extremes from healthy sample L 54–H 33 41 TCI USA 81+123 Students+subjects addiction treatment unit 100 47 TCI USA 587 Participants study of aging 50 37 TCI+NEO+SSS Germany 181 Alcoholics 76 48 TPQ Brazil 110 Alcoholics 100 46 TPQ Finland 193+138 Healthy individuals+alcoholic offenders 100 29 TPQ Germany 92 Alcoholics 100 44 TPQ Germany 190 Healthy students 100 34 TPQ Germany 136 Healthy individuals 35 26b TPQ Germany 276 Healthy volunteers 26 42 TPQ Ireland 47 College students ? 38 TPQ Israel 124 Healthy individuals 56 22b TPQ Israel 94 Volunteers 52 24b TPQ USA 341 Substance dependence+personality disorder+controls 60 30 TPQ USA 119 Healthy students 100 28b TPQ USA 281 Same-sexed twins 44 33 TPQ USA 455 Healthy individuals 40 35

aTCI=Temperament and Character Inventory, TPQ = Tridimensional Personality Questionnaire, SSS= Scale, KSP=Karolinska Scales of Personality, NEO-FFI = NEO Five Factor Inventory , NEO-PI-R=NEO Personality Inventory– Revised. bstudy showing significant association.

polymorphisms were observed.62 In people having at receptor agonist-induced reactivity had been asso- least one C-allele at the –521 C/T SNP, higher NS and ciated with the trait of positive emotionality.70 lower P was reported in individuals carrying long Association of three polymorphisms in DRD2 was alleles at the 48-bp VNTR when compared to observed with NS, RD and P as measured by TPQ.28 In individuals with only short alleles. a recent study using an extended battery of person- Another candidate gene from the dopamine path- ality tests, association with the DRD2 –141 C Ins/Del way is the dopamine transporter gene (DAT1). An polymorphism was reported for detachment as mea- extra motivation to test the association of DAT1 with sured by the Karolinska Scales of Personality (KSP) the dimension of NS was the finding that DAT1 was and lack of assertiveness as assessed by the Scandi- associated with attention-deficit hyperactivity disor- navian Universities Scales of Personality (SSP).71 In der (ADHD),63–65 a syndrome that bears some trivial two other studies, however, no association between analogies to NS behavior. In a first attempt to link DRD2 and temperament was detected.36,67 In a linkage DAT1 to NS, no association could be established.66 A study on families of alcoholics, the dimension of HA study on cigarette smoking behavior found associa- was linked to DRD2.49 tions of DAT1 with smoking status and with NS.67 The dopamine receptor D3 gene (DRD3) Neither association could be replicated in a subse- was included in a study using the TPQ73 and in a quent study.68 In a more recent study using the TCI, study using various personality inventories,74 but no DAT1 only showed association with the RD4 subscale association with any of the scales could be estab- measuring dependence vs independence.69 In a study lished. In a later study, association was detected using extremely high- and low-scoring individuals, between DRD3 and NS in a group of recovered BP association was reported between DAT1 and NS.41 patients.75 DRD3 was also reported to be associated to After stratification for gender, the effect was only neuroticism and behavioral inhibition in a sample of found in female subjects. 862 individuals. However, when the sample was The dopamine receptor D2 gene (DRD2) was extended to 1465 persons, the association could not considered a candidate gene, since dopamine D2 be replicated.76

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 843 In the latter study, the gene coding for catechol patients with bipolar disorder and healthy controls, O-methyltransferase (COMT), which is involved in but no association could be demonstrated.101 A study the degradation of dopamine, was examined in of five SNPs of 5-HT2A in a sample of healthy relation to various personality scales, but no associa- Japanese individuals failed to show association with tions were observed.76 any of the TCI dimensions.102 A point mutation in 5- HT2C was associated to the TPQ dimensions RD and Serotonin P, and in addition a significant interaction effect of The most frequently studied candidate gene from DRD4 and 5-HT2C on RD was detected.73 Attempting the serotonin pathway is undoubtedly the 5-HTT. to replicate these findings, Kuhn et al34 reported no Most studies focused on the insertion/deletion main effect of 5-HT2C on RD, but the results did polymorphism in the regulatory region of 5-HTT: the confirm the interaction effect of DRD4 and 5-HT2C on 5-hydroxytryptamine-linked polymorphic region RD. (5-HTTLPR).77 The short (s) allele (44-bp deletion) is transcribed less efficiently than the long (l) allele Noradrenaline (44-bp insertion), which results in a decreased 5-HTT The noradrenaline pathway is much less studied than expression and 5-HT uptake in lymphoblasts. Asso- the dopamine and serotonin systems. An exonic RFLP ciation was reported with anxiety-related traits: in the norepinephrine transporter (NET) was exam- individuals with the s/s or s/l genotypes had higher ined in a sample of healthy subjects, but no associa- scores on neuroticism and HA.78 A list of studies tions were obtained with any of the TCI temperament followed in which the effect was replicated in healthy scales or subscales.69 Polymorphisms in the a1a individuals79–82 and in patients with Parkinson’s adrenoceptor (ADRA1A) and a2a adrenoceptor disease.83 In some studies replication failed using (ADRA2A) genes did not show association with the healthy populations35,37,84–96 or affected indivi- TPQ dimensions in Chinese subjects.103 Another duals.47,88,97,98 Some studies obtained results in the study focusing on ADRA2A did find some associa- opposite direction, detecting associations of the s/s tions of a common SNP in ADRA2A with measures of and s/l genotypes with a lower mean score on the irritability, hostility and .104 subscale HA1,69 and with neuroticism.99 In a study of our group using extremely scoring individuals, the Transcription factor short allele was more frequent in the low-HA than in The AP-2b transcription factor is implicated in the high-HA group.41 Furthermore, associations were multiple pathways. Several genes encoding proteins reported between the 5-HTT polymorphism and in the dopaminergic, serotonergic and cholinergic cooperativeness,92,93 self-directedness92 and open- systems, such as the above-mentioned DAT1 and 5- 98 HTT, have AP-2 binding sites in their regulatory ness. Recently, it was shown by functional magnetic 105 resonance imaging that individuals carrying one or regions. This makes the AP-2b gene an interesting two copies of the short 5-HTTLPR allele exhibited candidate to look at. The authors studied a poly- greater amygdala neuronal activity in response to morphic region in the AP-2b gene and tested for fearful stimuli.100 This finding of genetically driven association with personality as measured by the KSP. differential excitability of the amygdala to emotional Associations were observed with the scales of stimuli renders further support for the claimed muscular tension and guilt. After stratification for association of the short 5-HTTLPR allele with gender, all anxiety-related scales showed association measures of anxiety. Table 2 summarizes an overview with the AP-2b polymorphism in female subjects, while in male subjects only the indirect aggression of the studies on the 5-HTTLPR and HA with some 105 details on the study design. scale was significantly associated. Some authors studied the possible association of anxiety-related traits with a VNTR polymorphism in Multivariate analyses intron 2 of the 5-HTT gene. No associations were Instead of examining one or few polymorphisms, the observed in studies using extremely scoring indivi- investigation of several genes simultaneously and duals on neuroticism89 and peer-rated neuroticism,84 their interactions seems more appropriate in the nor in a study using the KSP.91 However, the VNTR search for genes for complex traits. Benjamin was associated with the KSP scale measuring somatic et al35,106 studied three candidate genesFDAT1, anxiety in a group of female subjects.94 In a study on 5-HTT and COMTFand their interactions. Associa- Chinese subjects using the TPQ, the VNTR was tions of 5-HTT and COMT with the TPQ dimension P associated with scores on the HA2 subscale, measur- were observed, as well as an interaction effect of these ing fear of uncertainty vs confidence.95 When stratify- two genes. ing for gender, the latter association was found only in The largest study with respect to numbers of genes males subjects. is a study by Comings et al,47 in which 59 candidate Two other genes from the serotonin pathway were genes belonging to different neurotransmitters and studied in relation to personality: the serotonin hormonal pathways were tested for association with receptor 2A (5-HT2A) and the serotonin receptor 2C the seven TCI dimensions. Besides some single (5-HT2C) genes. A SNP in exon 1 of 5-HT2A was associations between one polymorphism and one tested for association with the dimension of HA in trait, the most important result was the involvement

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 844 Table 2 Overview of studies testing the association between the ins/del polymorphism in 5-HTT and anxiety-related traits

Inventory a Country Phenotypeb Participants Population % Males Ref.

F Germany Peer-rated NEUR 52–54 Extremes from twin sample ? 84 EPQ-R Australia NEUR 759 General population ? 87 KSP Sweden NEUR-related traits 127+178 General population 61, 48 91 KSP Sweden NEUR-related traits 251 Healthy individuals 0 94c NEO USA NEUR + est HA 397 General population 16 81c NEO + TPQ USA NEUR + HA 322 Substance dependence+personality 59 97 disorder+controls NEO-FFI Scotland NEUR 100–104 Extremes L 63–H 38 89 NEO-FFI USA NEUR 150 Individuals from alcoholism ?98 pedigrees NEO-PI + TCI Japan NEUR + HA 203 Healthy students 100 86 NEO-PI-R Japan NEUR 244 Healthy individuals 22 96 NEO-PI-R USA NEUR + est HA 221 Healthy individuals 93 78c NEO-PI-R USA NEUR + est HA 225 Adults 50 90 NEO-PI-R USA NEUR 202 Depressed geriatric patients+ ?99c non-depressed controls NEO-PI-R + TCI Japan NEUR + HA 144 Medical staff+students 42 93 NEO-PI-R + TPQ Israel NEUR + HA 148 Healthy individuals 34 82c SRQ-AD Japan Anxiety 189 Healthy individuals 62 80c TCI Poland HA 127 Healthy individuals 41 69c TCI Sweden HA 110+109 Extremesohealthy sample L 70–H 27 41c TCI USA HA 634 Volunteers 43 92 TCI USA HA 81+123 Students+subjects addiction 100 47 treatment unit TCI USA HA 425 Participants study of aging 51 37 TPQ China HA 192 Healthy volunteers 49 95 TPQ Finland HA 215+182 Healthy controls + alcoholic criminal ?88 offenders TPQ Israel HA 120 Healthy individuals 55 85 TPQ Israel HA 455 General population 40 35 TPQ Japan HA 101 Healthy individuals 61 79c TPQ USA HA 47+37 Parkinson+controls 66+46 83c

aTCI=Temperament and Character Inventory, TPQ=Tridimensional Personality Questionnaire, KSP=Karolinska Scales of Personality, SRQ-AD=Japanese self-rating questionnaire for anxiety and depression, NEO-PI-R=NEO Personality Inventory- Revised, NEO-FFI=NEO Five Factor Inventory, EPQ-R= Eysenck Personality Questionnaire. bNEUR=neuroticism, est HA=HA estimated from NEO. cstudy showing significant association.

of different ratios of functionally related groups tested using the TPQ. The genome scan included 291 in different traits. Moreover, with few exceptions, markers with an average distance of 13 cM. The each of the functional groups played a role in each dimension of HA was linked to a region on 8p21–23 of the seven traits. A negative aspect of the study (LOD ¼ 3.2, P ¼ 6 Â 10À5, without correction for multi- in terms of generalization is the population in which ple testing), explaining 38% of the variance. Sugges- these 59 genes were tested. The individuals in tions of epistasis were observed with loci on 18p, 20p the sample were 81 students and 123 subjects from and 21q. The linkage of HA to 8p21 was replicated in a veterans administration hospital addiction treat- an independent sample.108 ment unit. Furthermore, only male subjects were A large longitudinal study on anxious depression included in the test group. In fact, it would be was carried out in a set of Dutch families, who were preferred if such a general study could be conducted tested for several personality traits, including sensa- on a representative sample of mostly healthy indivi- tion seeking, neuroticism and extraversion.109 A duals from both sexes. second study focusing on anxiety and depression was performed on a large sample of Australian siblings and twins.110 In both studies, extremely Genome-wide scans concordant and discordant sibling and twin pairs Another approach to identify genes is a genome-wide were selected for genotyping in a genome-wide scan. analysis of linkage or association to the phenotype. Preliminary studies suggested several regions asso- The first published genome scan for personality was ciated with the trait of neuroticism.111,112 Very performed by Cloninger et al.107 A total of 758 sib recently, results of a linkage study using extremely pairs from 177 nuclear families of alcoholics were discordant and concordant sibling pairs identified

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 845 loci for neuroticism on 1q, 4q, 7p, 12q and 13q.113 The Replicability QTLs on chromosomes 1, 12 and 13 were likely to be A particular problem in the search for personality female specific. genes is the great diversity in study designs and the lack of replicability resulting most often from it. Problems Following the publication of the first positive find- ings on DRD4 and NS22,23 and on 5-HTT and HA,78 Personality measures several researchers used their existing materi- Many models exist to measure personality. Although alFsometimes patient materialFto try to replicate there are correlations between some of the scales of the published association. The studies differed the different inventories, for example, HA of the TCI widely in the composition of the sample, with regard and neuroticism of the NEO, each questionnaire to sex, ethnicity, age and health status. measures its specific personality traits. A comparison For some polymorphisms, the ethnicity of the of the three dimensions from the EPQ and the three participants is extremely important, as population original TPQ dimensions, revealed that they do not differences can exist. For example, several articles assess the same dimensions of personality.114 In reported large population differences in 5-HTT allele addition, it is important to examine the accuracy of frequencies.117,118 The frequency of the short allele the theories on which personality inventories were was 0.43 in the original paper78 and has remained the based. In the case of the psychobiological model, two same in subsequent studies on European, American remarks can be made. First, in their theory the authors and Australian samples. In the Japanese samples postulated that temperament would be highly heri- however, the frequency of the short allele ranges table, while character would be less heritable, but between 0.71 and 0.83.79,80,86,93,95,96 The frequency of more acquired.11 The study of Comings et al47 strongly the short 5-HTT allele in a small sample of African suggested that there is a comparable genetic contribu- American subjects was 0.24.97 In addition, up to 10 tion to the three character scales as to the four new alleles were discovered in the 5-HTT promoter temperament dimensions as measured by the TCI. polymorphism, some of which were only present in Also in a recent family study by our group, we found Japanese samples.118–122 Also the allele frequency equal heritability estimates for all TCI temperament distribution of the DRD4 48-bp VNTR differs widely and character scales.18 Second, in the biological part across ethnic groups.123 of the model, it is stated that each of the three original As is evident from studies in affected populations, temperament dimensions would be under the influ- personality can be greatly affected by the disease ence of a specific neurotransmitter system: NS and status. A prominent example is the measurement of dopamine, HA and serotonin and RD and noradrena- personality in depressed patients. In many studies, a line.10 As far as the molecular–genetic studies are clear state effect of depression on personality mea- concerned, these hypotheses are not unequivocally sures is seen, for example, an increase in HA or supported. The picture that emerged from the study neuroticism, dependency needs and self-transcen- results reflects a mixture and interplay of all neuro- dence and a decrease in extraversion, reward depen- transmitter systems on all measures. The genes from dence, self-directedness and cooperativeness.124,125 the noradrenaline system, although not extensively Also a comparison between schizophrenia patients studied yet, gave no clear associations with and healthy controls revealed important differences personality. in TCI scores.126 Therefore, we believe that all Generally, personality questionnaires are in a yes/ participants in a genetic study on personality should no format, with scales and subscales being built by be interviewed by a trained clinician to exclude major adding the number of times the answer ‘yes’ was neuropsychiatric disorders, such as affective and given on certain questions. A subscale or usually psychotic disorders. In addition, we advocate the is constructed by adding a few items, which leads to a use of individuals who have been sampled specifi- categorical rather than a continuous measure. The fact cally for participating in a genetic personality project. that scales are constructed by adding facets can be considered a disadvantage in the search for genes. It Multiple testing cannot be excluded that the scales, although con- Multiple testing is another problem with which the structed to be homogeneous on a psychological level, field of personality genetics has to cope continuously. represent a sum of traits with a different biological In most studies, a polymorphism is tested for background. Several studies have demonstrated that association with a number of personality scales and the structure of the seven TCI dimensions is not valid subscales, and often in a second step the sample is in all populations.18,37,115,116 We could take a step back stratified for example, by gender, and reanalyzed. and look at the scores on facets. As long as we want to This should not pose a major problem if the establish simple associations, this poses no major significance level of 5% is correctly adjusted for the problems. However, in QTL linkage analysis, most number of tests performed. The argument, however, programs assume that the quantitative trait under used by several researchers to explain why they did study is normally distributed. As mentioned above, not apply a correction for multiple testing, is that they scores on facets are mostly far from normally had prior hypotheses. This does not hold true in all distributed. cases.

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 846 We counted the number of tests performed and the cover some of the important genetic and environ- number of significant (Po0.05) associations found in mental variables and the possible gene–environment studies that used a candidate gene approach. In a total interactions. of 64 studies, in which the authors tested 1414 possible effects, 230 associations were found, which Conclusion means 16.3% significant results (see Appendix for overview). This percentage is higher than the ex- Over time and mainly concentrating on whether or pected error rate of 5%. This increase could be not a certain association is significant or not, one considered as a proof of the success of the candidate sometimes forgets the basic question of why we want gene association approach in the search for person- to unravel the genetics of personality, a purpose that ality genes. On the other hand, the overview is based is still two-fold. On the one hand, we want to identify on the results as they were presented in the article. It genes for personality in order to increase our knowl- is possible that some authors tested more associations edge of normal and abnormal personality or so-called than the ones they reported. Furthermore, we can personality disorders. It has been demonstrated that assume that the number of studies where no associa- normal personality and personality disorders are on tion was found is larger, keeping in mind the the same continuum,134 and therefore it is expected publication bias towards studies with positive results. that knowledge of the biological mechanisms acting If, however, we assume that 16% of the tested in normal personality can contribute to understand- associations were indeed significant, it remains a ing personality disorders. On the other hand, by question as to which ones ought to be followed up, as studying normal personality, we want to identify we do not know which associations represent true candidate genes for psychiatric disorders, such as effects and which are false-positive results. bipolar disorder, ADHD and substance dependence. If appropriate candidate genes can be discovered, the yand the environment? ultimate goal is to develop drugs that act on specific Almost by definition, complex traits originate from targets. Today however, the shortcut through person- interplay between (multiple) genetic factors and ality genetics seems to be as long as the road itself, environment. In the case of personality, everybody and unraveling the genetic background of personality seems to agree on the important influence of the has become a hard-to-reach target by itself. environmentFtwin studies consistently show that Can problems in the search for personality genes, environment explains about 50% of the varian- such as lack of uniformity in modeling and measuring ceFbut few consider environmental variables in the phenotype, and difficulties in replicating the their studies. Ozkaragoz and Noble127 described a usually small effects, be overcome? A major hin- good example of gene–environment interaction. They drance to significant progress in the field is lack of a showed that children of alcoholic parent(s) scored uniform phenotype. The choice between available significantly higher on extraversion if carrying spe- personality inventories is often not based on rational cific DRD2 genotypes. No main effects of the genetic grounds, but on emotional or personal preferences, or environmental variables on the personality trait of such as degree of familiarity with a certain ques- extraversion were seen. More recently, it was detected tionnaire or its designer. Progress can only be made if in a longitudinal study on boys that the interaction all researchers in the field orient their efforts in the between a functional polymorphism in the promoter same or at least similar direction. A possible starting of the monoamine oxidase A gene and the environ- point in developing a uniform phenotype might be mental factor of childhood maltreatment significantly the collection of large data sets obtained using major contributed to the development of antisocial problem personality inventories. Factor analyses on pooled behavior.128 Both studies illustrate how in some cases data on a subscale or even item level might result in a a genetic effect can be detected only when taking into number of independent personality factors. Or per- account the appropriate environmental variables. haps research performed in animal studies can The major question is which environmental vari- inspire us. Although personality as such is hard to ables one should study in relation to personality. In assess in animals, behaviors referring to approach analogy to the candidate gene approach, in which 20 (exploration) and avoidance (anxiety) are being or more genes are selected out of the 30 000 possible studied. Flint et al135 identified three loci influencing genes, ‘candidate environments’ could be chosen. emotionality in mice. In a study using DRD4 knockout Parenting style seems to be a plausible candidate mice, the mice displayed a significant decrease in variable. In a recent study, individuals who reported novelty-related behavior as compared to wild-type lower parental care and higher parental intrusiveness mice.136 In analogy, human personality could be were more likely to be higher in neuroticism, lower in assessed by experimental designs rather than using conscientiousness, lower in SD and higher in HD.129 self-report questionnaires. It does not seem unrealis- Other examples of environmental variables that have tic to develop experimental paradigms in which been reported to affect personality include season of behaviors linked to personality characteristics such birth130,131 and childhood sexual abuse.132,133 A multi- as HA or extraversion can be reliably tested. disciplinary approach in which geneticists and Evidently, the advantages of self-report inventories epidemiologists join a collaborative effort could un- are crystal clear: it is a relatively inexpensive and

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven 847 rapid way of obtaining personality measures of a large candidate genes are identified for further genetic number of people. The disadvantages are also well studies. Whatever design is used, large samples will known: biases such as social desirability tendency be needed to demonstrate functional links between often influence the results, and the longitudinal genes and personality since one can expect that genes stability of personality scores is far from perfect. If implicated in personality will have small effects. this fairly easy method of applying self-report In conclusion, we advocate that the field of inventories does not lead to the main goalFthe personality genetics will only be successful in identification of genes for personalityFperhaps a identifying genetic factors if one uses core pheno- change in methodology might be worthwhile con- types, large groups of healthy individuals, multiple sidering. genetic markers in functional and/or positional Another potential approach is using biomarkers. In candidate genes and includes environmental vari- a study by Farde et al,137 the density of DRD2 in brain ables. These goals can only be met if one continues was associated with detached personality. In a more integrating expertise from , epidemiology recent study, a negative correlation was established and molecular biology. between the binding potential values of extrastriatal DRD2 in the right insular cortex and NS scores on TCI.138 Furthermore, a small P3 event-related poten- Acknowledgements tial was associated with high sensation seeking139 and We acknowledge Jurgen Del-Favero and Stephan low self-directedness.140 Another biochemical marker Claes for critical reading of the manuscript, and the under study is platelet MAO activity, which was VIB Genetic Service Facility (http://www.vibgenetic- associated with neuroticism and variation in smoking servicefacility.be/) for their skillful genetic analyses. habits,141 sensation seeking and other personality The research in the author’s laboratory is funded by traits.142–144 If biomarkers can be correlated with the Fund for Scientific Research Flanders (FWO-F), personality traits, these markers might be used in the Special Research Fund of the University of the search for personality genes. A next step then Antwerp and the Interuniversity Attraction Poles would be a genome-wide search on a large set of (IUAP) program P5/19 of the Federal Office of healthy families using a dense map of genetic markers Scientific, Technical and Cultural Affairs (OSTC), and biomarkers as phenotypes. In this scenario, Belgium. SVG is a PhD fellow of the FWO-F. suitable biomarkers might be considered as endophe- notypes for personality. Having reviewed the literature, we can reflect on References what could be the best design for isolating genes for 1 Strelau J. Temperament: a Psychological Perspective. Plenum personality. There are basically two potential designs Press: New York, 1998. in genetic studies using either the association or 2 Loehlin JC, Nichols RC. Heredity, Environment, and Personality. linkage approach. Almost all previous genetic studies University of Texas Press: Austin, 1976. of personality used the association approach, that is, 3 Benjamin J, Ebstein RP, Lesch KP. 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Table A1

Reference a Gene b Traits c Tested d Signif e

Auerbach et al 52 (1999) DRD4, 5-HTT IBQ 40 11 Auerbach et al 53 (2001) DRD4, 5-HTT Temp episodes 15 6 Ball et al 84 (1997) 5-HTT (2) Peer-rated NEUR 2 0 Benjamin et al 23 1996 DRD4 NEO + est NS 22 10 Benjamin et al 35 (2000) DRD4, 5-HTT, COMT NS, HA, RD, P 24 4 Bookman et al 61 (2002) DRD4 (2) NEO-FFI 19 3 Brummett et al 99 (2003) 5-HTT NEO-PI-R 5 1 Comings et al 104 (2000) ADRA2A Various scales 23 9 Damberg et al 105 (2000) AP-2b KSP 45 7 Deary et al 89 (1999) 5-HTT (2) NEO-FFI 1 0 Ebstein et al 22 (1996) DRD4 NS, HA, RD, P 10 2 Ebstein et al 85 (1997) 5-HTT TPQ 4 0 Ebstein et al 24 (1997) DRD4 NS, HA, RD, P 8 2 Ebstein et al 73 (1997) 5-HT2C, DRD3, DRD4 TPQ 40 8 Ebstein et al 51 (1998) DRD4, 5-HTT NBAS 49 23 Ekelund et al 50 (1999) DRD4 NS 1 1 Ekelund et al 59 (2001) DRD4 NS 1 0 Flory et al 90 (1999) 5-HTT NEO-PI, est TPQ 28 0 Gebhardt et al 36 (2000) DRD2, DRD4 NS, HA, RD, P 12 0 Gelernter et al 30 (1997) DRD4 NS 2 0 Greenberg et al 81 (2000) 5-HTT NEO, 16PF, est TPQ 40 13 Gustavsson et al 91 (1999) 5-HTT KSP 8 0 Hamer et al 92 (1999) 5-HTT TCI 24 10 Henderson et al 76 (2000) COMT, DRD3 Various scales 27 8 Herbst et al 37 (2000) DRD4, 5-HTT TCI 35 0 Jo¨nsson et al 31 (1997) DRD4 5 KSP scales 25 2 Jo¨nsson et al 40 (2002) DRD4 (2) Various scales 46 0 Jo¨nsson et al 74 (2003) DRD3 Various scales 99 5

Molecular Psychiatry Genetics of personality: are we making progress? S Van Gestel and C Van Broeckhoven

852 Table A1 (continued)

Reference a Gene b Traits c Tested d Signif e

Jorm et al 87 (1998) 5-HTT Various scales 14 0 Jorm et al 68 (2000) DAT1 BIS/BAS + EPQ-R 15 0 Katsuragi et al 79 (1999) 5-HTT TPQ 2 2 Katsuragi et al 72 (2001) DRD2 TPQ 6 0 Kuhn et al 34 (1999) DRD4, 5-HT2C NS, HA, RD, P 9 1 Kumakiri et al 93 (1999) 5-HTT NEO-PI-R, TCI 12 1 Kusumi et al 102 (2002) 5-HT2A TCI 7 0 Lakatos et al 54 (2003) DRD4, 5-HTT IBQ + observations 54 5 Lee et al 62 (2003) DRD4 (2) TCI 12 2 Lesch et al 78 (1996) 5-HTT NEO, 16PF + est TPQ 50 15 Malhotra et al 29 (1996) DRD4 NS, HA, RD, P 4 0 Mazzanti et al 88 (1998) 5-HTT TPQ 15 2 Melke et al 94 (2001) 5-HTT (2) KSP 20 8 Mitsuyasu et al 39 (2001) DRD4 (6) NS, HA, RD, P 24 1 Murakami et al 80 (1999) 5-HTT SRQ-AD 2 1 Nakamura et al 86 (1997) 5-HTT 7 TCI + 5 NEO dim 12 0 Noble et al 28 (1998) DRD2 (3), DRD4 NS, HA, RD 90 19 Okuyama et al 57 (2000) DRD4 (6) NS, HA, RD, P 24 1 Ono et al 25 (1997) DRD4 TCI 5 1 Osher et al 82 (2000) 5-HTT TPQ +NEO 19 4 Persson et al 60 (2000) DRD4 NEO-PI-R 5 0 Pogue-Geile et al 33 (1998) DRD4 (2) Various scales 84 1 Ronai et al 58 (2001) DRD4 NS, HA, RD, P 12 1 Sabol et al 67 (1999) DAT1 NS, HA, RD, P +NEO 9 1 Samochowiec et al 69 (2001) DAT1, NET, 5-HTT NS, HA, RD, P 45 2 Stoltenberg et al 98 (2002) 5-HTT NEO scales 15 2 Strobel et al 26 (1999) DRD4 Various scales 62 23 Strobel et al 42 (2002 ) DRD4 (2) TPQ 7 0 Strobel et al 43 (2003) DRD4 (2) NEO-FFI + est NS 42 0 Swift et al 38 (2000) DRD4 NS, HA, RD, P 4 0 Tomitaka et al 27 (1999) DRD4 NS, HA, RD, P 8 3 Tsai et al 103 (2001) ADRA1A, ADRA2A TPQ 14 0 Tsai et al 95 (2002) 5-HTT (2) TPQ 14 1 Umekage et al 96 (2003) 5-HTT NEO-PI-R 15 0 Vandenbergh et al 32 (1997) DRD4 est NS 3 0 Van Gestel et al 41 (2002) DRD4, DAT1, 5-HTT NS, HA 24 8 1414 230

aonly the healthy individuals are included. bnumber in () indicates number of polymorphisms tested in the gene, if >1. c16PF=16 Personality Factors Inventory, BIS/BAS=Behavioral Inhibition System/Behavioral Activation System Question- naire, EPQ-R= Eysenck Personality Questionnaire-Revised, IBQ=Rothbart’s Infant Behavior Questionnaire, KSP=Karolinska Scales of Personality, NBAS=Brazelton neonatal assessment scale, NEO-FFI=NEO Five Factor Inventory, NEO-PI-R=NEO Personality Inventory-Revised, SRQ-AD=Japanese self-rating questionnaire for anxiety and depression, TCI=Temperament and Character Inventory, TPQ=Tridimensional Personality Questionnaire, NS=novelty seeking, HA=harm avoidance, RD=reward dependence, P=persistence, est=estimated from NEO, NEUR=neuroticism, temp episodes=temperament episodes eliciting fear, anger, pleasure, interest and activity in infants. dnumber of associations tested, interaction effects included. enumber of tested associations that were significant.

Molecular Psychiatry