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Andreas Reif, Klaus-Peter Lesch - Toward a Molecular Architecture of Personality

Andreas Reif, Klaus-Peter Lesch - Toward a Molecular Architecture of Personality

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Epidemiological studies provided a large body of evidence that personality dimensions are influenced by genetic factors and that
the genetic component is highly complex, polygenic, and epistatic. However, consistent findings on the genetic basis of personality
have yet remained sparse. In recent years, molecular genetics has begun to identify specific genes coding in particular for
components of the serotonergic and dopaminergic neurotransmitter systems representing quantitative trait loci (QTLs) for
behavioral traits. The QTL concept suggests that complex traits are not attributable to single genes. According to this polygenic
model, the genetic basis of personality and behavior and its pathological variations thus results from additive or nonadditive
interactions of various genes. As the number of suitable candidate genes constantly increases, the QTL model provides a reasonable
explanation for the genetic basis of personality and its disorders. In this review, the current knowledge on the impact of a large
number of candidate gene polymorphisms (e.g. variations in serotonin and dopamine receptor and serotonin transporter genes) on
personality and temperament is summarized. Additionally, investigations of gene/gene and gene/environment interactions in
humans and animals, which currently intensify the identification of genes that underlie behavioral variations, are examined. The
findings converge on the notion that a probabilistic rather than deterministic impact of genes on the expression of behavior will
contribute to the demystification of behavioral disorders.
# 2002 Elsevier Science B.V. All rights reserved.
Epidemiological studies provided a large body of evidence that personality dimensions are influenced by genetic factors and that
the genetic component is highly complex, polygenic, and epistatic. However, consistent findings on the genetic basis of personality
have yet remained sparse. In recent years, molecular genetics has begun to identify specific genes coding in particular for
components of the serotonergic and dopaminergic neurotransmitter systems representing quantitative trait loci (QTLs) for
behavioral traits. The QTL concept suggests that complex traits are not attributable to single genes. According to this polygenic
model, the genetic basis of personality and behavior and its pathological variations thus results from additive or nonadditive
interactions of various genes. As the number of suitable candidate genes constantly increases, the QTL model provides a reasonable
explanation for the genetic basis of personality and its disorders. In this review, the current knowledge on the impact of a large
number of candidate gene polymorphisms (e.g. variations in serotonin and dopamine receptor and serotonin transporter genes) on
personality and temperament is summarized. Additionally, investigations of gene/gene and gene/environment interactions in
humans and animals, which currently intensify the identification of genes that underlie behavioral variations, are examined. The
findings converge on the notion that a probabilistic rather than deterministic impact of genes on the expression of behavior will
contribute to the demystification of behavioral disorders.
# 2002 Elsevier Science B.V. All rights reserved.

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Re
v
iew article
Toward a molecular architecture of personality
Andreas Reif *, Klaus-Peter Lesch
Department of Psychiatry and Psychotherapy, Uni 
v
ersity of Wuerzburg, Fu¨ chsleinstr. 15, 97080 Wuerzburg, Germany
Recei
v
ed 22 May 2002; recei
v
ed in re
v
ised form 15 August 2002; accepted 15 August 2002
Abstract
Epidemiological studies pro
v
ided a large body of e
v
idence that personality dimensions are influenced by genetic factors and thatthe genetic component is highly complex, polygenic, and epistatic. Howe
v
er, consistent findings on the genetic basis of personalityha
v
e yet remained sparse. In recent years, molecular genetics has begun to identify specific genes coding in particular forcomponents of the serotonergic and dopaminergic neurotransmitter systems representing quantitati
v
e trait loci (QTLs) forbeha
v
ioral traits. The QTL concept suggests that complex traits are not attributable to single genes. According to this polygenicmodel, the genetic basis of personality and beha
v
ior and its pathological
v
ariations thus results from additi
v
e or nonadditi
v
einteractions of 
v
arious genes. As the number of suitable candidate genes constantly increases, the QTL model pro
v
ides a reasonableexplanation for the genetic basis of personality and its disorders. In this re
v
iew, the current knowledge on the impact of a largenumber of candidate gene polymorphisms (e.g.
v
ariations in serotonin and dopamine receptor and serotonin transporter genes) onpersonality and temperament is summarized. Additionally, in
v
estigations of gene
 Á 
/
gene and gene
 Á 
/
en
v
ironment interactions inhumans and animals, which currently intensify the identification of genes that underlie beha
v
ioral
v
ariations, are examined. Thefindings con
v
erge on the notion that a probabilistic rather than deterministic impact of genes on the expression of beha
v
ior willcontribute to the demystification of beha
v
ioral disorders.
#
2002 Else
v
ier Science B.V. All rights reserved.
Keywords:
Beha
v
ioral genetics; Candidate genes; Serotonin transporter; 5-HTT; Dopamine receptor; DRD4; Polymorphism; Quantitati
v
e trait loci
1. Introduction
Personality is generally defined as the characteristicmanner and style of an indi
v
idual’s beha
v
ior andencompasses
v
igor, temper, and persistence of theresulting beha
v
ior[12]. Se
v
eral models of humanpersonality do exist, especially with respect to the ‘basic
v
ariablesor beha
v
ioral dimensions which shape per-sonality traits. Examples are the seminal models pro-posed by Eysenck (measured by Eysenck’s PersonalityQuestionnaire EPQ), Cloninger (which in
v
ol
v
es threebasic dimensions, measured by the TridimensionalPersonality Questionnaire TPQ;[31]) and McCostaand Crae; the latter concept in
v
ol
v
es fi
v
e basic dimen-sions dubbed the ‘Big Fi
v
e’ and is quantified using theNEO-PI-R questionnaire[42]. Se
v
eral other ratingscales and models do exist, with
v
arying importanceand impact; howe
v
er, there is considerable agreementbetween different personality measurements used[51].Human personality is shaped by both genetic factorsas well as en
v
ironmental influences, and the proportionbetween both
v
aries for different traits, with some traitsha
v
ing a substantial genetic impact, whilst others areinfluenced more by en
v
ironment[146]. The apparentheterogeneity of both genetic and en
v
ironmental deter-minants predicts the ineffecti
v
eness of searching forunitary causes, so that dimensional and quantitati
v
eapproaches to personality and beha
v
ioral genetics wereincreasingly applied in the recent years. While quanti-tati
v
e genetics has focused on complex, quantitati
v
elydistributed traits caused by multiple genetic and en
v
ir-onmental factors, molecular genetics has begun toidentify specific genes for quantitati
v
e traits, calledquantitati
v
e trait loci (QTLs)[63]. In this polygenicmodel, beha
v
ior and personality are dissected intose
v
eral dimensional traits determined by
v
arious geneswhich interact either additi
v
ely or nonadditi
v
ely.
* Corresponding author. Tel.:
'
/
49-931-201-7600; fax:
'
/
49-931-201-7755; www.uni-wuerzburg.de/ner
v
enklinik/Staff.html
E-mail address:
a.reif@gmx.net(A. Reif).Beha
v
ioural Brain Research 139 (2003) 1
 Á 
/
20www.else
v
ier.com/locate/bbr0166-4328/02/$ - see front matter
#
2002 Else
v
ier Science B.V. All rights reserved.PII: S0166-4328(02)00267-X
 
This re
v
iew discusses the current knowledge on themolecular basis of personality, its
v
ariations and dis-orders and focuses on topics undergoing particularlyrapid progress. Since they play a critical role in theappraisal of empirical findings in beha
v
ioral genetics,conceptual and methodological issues related to thesearch for candidate genes will also be considered.
2. Personality disorders: distinct categories or dimensionsof human behavior?
‘Personality disorder’ (PD) is an umbrella term co
v
er-ing
v
arious conditions characterized by a persistentpattern of abnormal beha
v
ior, social dysfunctioning,and suffering of either the indi
v
idual and/or theen
v
ironment. Despite problems of classification, epide-miological research in
v
ol
v
ing family, twin, and adopteestudies has accrued persuasi
v
e e
v
idence that se
v
eralcategories of PD are influenced by genetic factors andthat the genetic component is highly complex, polygenic,and epistatic[41,62,86,93,122]. The diagnosis of PD ise
v
idently not as clear-cut as the geneticist would desire,which might lead to spurious findings due to ill-definedphenotypes
 * 
/
a problem encountered frequently in be-ha
v
ioral and psychiatric genetics, as thoroughly definedphenotypes are of paramount importance in geneticresearch[145].The DSM-IV[3]criteria of PD are (I), a persistentpattern of abnormal beha
v
ior, (II), dysfunctioning insocial contexts, (III), suffering of either the patient and/or the en
v
ironment, and (IV), early onset in childhoodor adolescence. This definition co
v
ers a wide range of disorders which might be subdi
v
ided in almost infinitedifferent ways. It is notable that PDs not only depend onthe patient, but also the social context, which is of substantial importance when this diagnosis is applied;indi
v
iduals functioning perfectly in some societies mayfail to do so in others. Accordingly, PD, in part, lies inthe eye of the beholder. These e
v
ident problems regard-ing the nosology of PDs hamper the identification of underpinning genetic influences.To complicate matters further, there is a considerabledebate whether PDs are distinct disease entities orextreme
v
ariations of ‘normal’ personality traits, follow-ing a Gaussian distribution[150]. The latter
v
iew, whichwas initially proposed by Schneider, Kretschmer, Krae-pelin and modified later by Leonhard who put forwardthe idea of a continuum from normal to accentuated andfinally disordered personality[105], pro
v
ides a rationalefor the in
v
estigation of candidate genes in normalpersonality and PDs alike, and initial studies ha
v
ealready started to pro
v
e this idea[85].According to this concept, PDs could be
v
iewed as an e
v
olutionarystrategy to adapt to different en
v
ironmental conditions.Abnormal beha
v
ior and dysfunctioning might be correctattributes for a certain kind of personality in a gi
v
enculture; but cultures and societies
v
ary and constantlychange, and what was dysfunctional yesterday might besuccessful today. PDs therefore may be the pricemankind has to pay for its flexibility to rapidly adaptto different en
v
ironments. Importantly, the genes under-lying beha
v
ioral traits ha
v
e been shaped throughoute
v
olution in order to succeed in primordial and not incontemporary societies. Humans still bear the constrainsof this genetic background, and some of the featuresnow regarded as ‘disordered’, like exaggerated anxiety,no
v
elty seeking (NS), and risk taking hyperacti
v
ity orstraightforward aggression, might represent strategiesthat were highly successful in ancient times.Distinct PDs as categorized in DSM-IV do notrepresent a categorical unit of human beha
v
ior butrather a blend of temperamental traits, cogniti
v
e plans,mental ‘master’ attitudes, patterns of beha
v
ior and soon. Some of these features ha
v
e a substantial geneticcomponent, while others ha
v
e not. Due to the hetero-geneity of PD diagnoses, it appears to be naı¨
v
e and futileto search for a single genetic cause resulting in a specificPD. Rather, personality traits underlying PDs should beidentified and then be in
v
estigated for genetic contribu-tions.
3. The genetic dissection of personality
Human personality, apart from en
v
ironmental influ-ences, is a multi-gene product. Beha
v
ioral traits arepolygenic, so that classical genome-wide linkage ana-lyses fail to detect the genes accounting for personalitytraits. Accordingly, there are only a few studies employ-ing this technique in personality genetics, and they wereconducted in alcoholics which restricts the findings. Astudy deri
v
ed from the Collaborati
v
e Study on theGenetics of Alcoholism data set indicated that theTPQ trait NS and alcoholism share a strong geneticassociation and suggested a QTL on chromosome 4[45].Another linkage analysis in nuclear families of alco-holics was conducted by Cloninger et al., who alsoutilized the TPQ questionnaire[32]. This group detectedsignificant linkage between Harm A
v
oidance and alocus on chromosome 8p21
 Á 
/
23, explaining 38% of thetrait
v
ariance. Epistatic interactions could be foundbetween this and other loci located on chromosome 18p,20p, and 21q. Other personality traits seemed to beunder epistatic influence as well. Howe
v
er, it is unclearwhether these results, obtained from alcoholic families,can be transferred to healthy subjects. Similar studiesare unfortunately not a
v
ailable in ‘normalcontrols,albeit under way[94].Matters are getting e
v
en more complicated whengene
 Á 
/
en
v
ironment and gene
 Á 
/
gene interactions are ta-ken into account. A polymorphism which is associated
A. Reif, K.-P. Lesch / Beha
v
ioural Brain Research 139 (2003) 1
 Á 
 20
2
 
with a PD in one population may not be in anotherethnic group
 * 
/
a problem which is increasingly beingappreciated in beha
v
ioral genetics and which mightexplain a substantial number of equi
v
ocal findingsgathered on specific genetic
v
ariations in differentstudies. Since the phenotypic effect of a gi
v
en genetic
v
ariation is only small, and because the power of linkageanalysis to detect small gene effects is quite limited, QTLresearch is relying on sensible, presumably functionalcandidate genes. Both pleiotropy and epistasis play acritical role in the molecular basis of personality, andpersonality traits seem to be defined by sets of at least10
 Á 
/
20 different genes. Se
v
eral methods to map genes incomplex human diseases do exist, e.g. associationstudies and se
v
eral different linkage analyses. E
v
eryapproach has both ad
v
antages and disad
v
antages; thediscussion of these are beyond the scope of this re
v
iew,yet the interested reader might be referred to furtherliterature[142].In addition to ‘human-basedapproaches, micestrains selecti
v
ely bred to display a phenotype of interestare currently used to identify genetic loci that contributeto beha
v
ioral traits. The QTL approach has beenapplied with some success to a trait in mice called‘emotionality’[64]; three QTL regions that appeared tobe related to
v
arious measures of fearfulness thus couldbe identified. Regrettably, linkage analyses only pro
v
idea rough chromosomal localization, whereas positionalcloning remains challenging[179]. Since mice andhumans share many orthologous genes mapped tosynthenic chromosomal regions, it is concei
v
able thatthe combination of elaborate genetic and beha
v
ioralanalyses results in the generation of candidate genes forhuman beha
v
ioral disorders.
4. Candidate genes for personality
A hypothesis-dri
v
en and hence powerful complemen-tary approach to quantitati
v
e genetic studies are in-
v
estigations whether certain candidate genes arein
v
ol
v
ed in the manifestation of a specific phenotype.Psychobiology meanwhile has accrued thorough knowl-edge of neurotransmitter networks, and consequentlythe first candidate genes in
v
estigated were componentsof the monoamine neurotransmitter pathways. Almostno information is yet a
v
ailable on the role of constitu-ents of messenger pathways or transcription factors.
4.1. The serotonergic system
Con
v
erging lines of e
v
idence indicate that the seroto-nergic system is in
v
ol
v
ed in brain de
v
elopment andsynaptic plasticity. Temperamental predisposition andbeha
v
ior are likely to be influenced by genetic
v
ariationsof serotonergic genes. The central 5HT system isthought to function as a beha
v
ioral inhibition systemand is in
v
ol
v
ed in the regulation of food intake,circadian rhythms, mood, anxiety, aggression and im-pulsi
v
ity. It exerts its actions by modulation of 
v
ariousother transmitter systems, and it integrates and connectsthose spatially separated systems. It thus forms a globalmeta-network of distinct local networks, thereby co-ordinating and balancing brain functions.Serotonergic dysfunction has been implicated in
v
arious psychiatric disorders[114]. A pi
v
otal role of the serotonergic system has been hypothesized in thepathogenesis of Borderline PD; low 5HT concentrationsor turno
v
er are correlated with suicide, impulsi
v
ity,aggression, and
 * 
/
in neonatals
 * 
/
with a family history of antisocial PD[40]. In line with these findings, patientssuffering from se
v
ere PDs of the high aggression/lowimpulse control-type (e.g., antisocial PD) exhibit de-creased le
v
els of the 5HT metabolite 5HIAA[22,23]. Ina landmark study by Raleigh et al.[151], it wasdemonstrated that male monkeys with low social statusalso ha
v
e low CSF 5HIAA concentrations. Correspond-ingly, high 5HIAA le
v
els were associated with highsocial status. Intriguingly, pharmacological alterationsof serotonergic function influenced the social rankwhich further underscores the critical role 5HT playsin controlling temperament and beha
v
ioral traits.Hence, 5HT appears to be a stabilizer of neural aswell as social networks.
4.1.1. Serotonin metabolism
5HT is synthesized in a two-step reaction fromtryptophan. The rate-limiting step is catalyzed bytryptophan hydroxylase (TPH) and is restricted to rapheneurons. Up to now, 14 5HT receptor subtypes areknown. The re-uptake of extracellular 5HT is performedby the selecti
v
e 5HT transporter (5HTT). 5HT there-after is recycled for repetiti
v
e release or degraded to5HIAA by monoamine oxidase A (MAO-A). Forse
v
eral of the genes in
v
ol
v
ed the serotonergic pathway,polymorphisms ha
v
e been identified that may influencepersonality traits and related disorders.
4.1.2. Tryptophan hydroxylase
The TPH gene has been assigned to chromosome11p15.3
 Á 
/
p14[43]. Besides polymorphisms in the up-stream regulatory region, intron 7 is the site of two
v
ariations, with elusi
v
e functional rele
v
ance[129]. Bothare A to C trans
v
ersions at the base pairs 218 and 779,respecti
v
ely. 779A is termed allele U, and 779C allele L.Since low 5HT system function is known to correlatewith aggression and impulsi
v
ity, a link between TPHgene
v
ariants and these traits had been predicted.In a pioneering study, it was shown that the L
v
ariantis associated with decreased CSF 5HIAA concentrationsand that this polymorphism may predispose to suicidalbeha
v
ior[128]. Howe
v
er, no association with impulsi
v-
A. Reif, K.-P. Lesch / Beha
v
ioural Brain Research 139 (2003) 1
 Á 
 20
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