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DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 103 C l i n i c a l r e s e a r c h The genetic epidemiology of personality disorders Ted Reichborn-Kjennerud, MD, PhD T he introduction of personality disorders (PDs) as diagnostic categories on a separate axis (Axis II) in the third edition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-III) in 19801had a dramatic effect on the level of interest in these disorders among researchers, and the number of published articles increased substantially. However, the number of genetic epidemiologic studies of the DSM PDs has remained limited compared with studies on both clinical disorders like schizophrenia, depression, and anxiety disorders (which are classified on Axis I in DSM), and on normal Genetic epidemiologic studies indicate that all ten per- personality traits.2-4 sonality disorders (PDs) classified on the DSM-IV axis II The understanding of the role of genetic factors in the are modestly to moderately heritable. Shared environ- etiology of disorders and traits is inseparably linked to mental and nonadditive genetic factors are of minor or classification, since a precise definition of the phenotype no importance. No sex differences have been identified. is a prerequisite for all successful genetic studies. In this Multivariate studies suggest that the extensive comor- review we will focus on PDs as they are classified in the bidity between the PDs can be explained by three com- DSM; a system that serves many purposes, and is not mon genetic and environmental risk factors. The genetic specifically designed for genetic studies. This is a prob- factors do not reflect the DSM-IV cluster structure, but lem not only for the genetics of PDs, and the search for rather: i) broad vulnerability to PD pathology or nega- better phenotypes for genetic studies of mental disorders tive emotionality; ii) high impulsivity/low agreeableness; is especially well illustrated in the literature on schizo- and iii) introversion. Common genetic and environmen- phrenia (eg, refs 5, 6). tal liability factors contribute to comorbidity between The goal of psychiatric genetic epidemiology is to under- pairs or clusters of axis I and axis II disorders. Molecular stand the role of genetic and environmental factors in genetic studies of PDs, mostly candidate gene association the etiology of mental disorders.7In this paper we will studies, indicate that genes linked to neurotransmitter focus mainly on the genetic factors. After a brief outline pathways, especially in the serotonergic and dopamin- of the current DSM axis II PD classification, we will ergic systems, are involved. Future studies, using newer methods like genome-wide association, might take Author affiliations: Division of Mental Health, Norwegian Institute of advantage of the use of endophenotypes. Public Health Institute of Psychiatry, University of Oslo, Norway; Department of Epidemiology, Columbia University, New York, NY, USA © 2010, LLS SAS Dialogues Clin Neurosci.2010;12:103-114. Address for correspondence:Ted Reichborn-Kjennerud, Director, Department of Keywords:personality disorder; axis I disorder; genetics; twin study; molecular Adult Mental Health, Norwegian Institute of Public Health, Box 4404 Nydalen, genetic study; candidate gene N-0403 Oslo, Norway (e-mail: [email protected]) Copyright © 2010 LLS SAS. All rights reserved 103 www.dialogues-cns.org DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 104 C l i n i c a l r e s e a r c h evaluate the evidence for genetic influences on PDs and tor structure.15One of the most controversial and long- examine quantitative genetic studies that explore the standing issues in the field of PD classification is, how- specificity of the genetic effects, ie, to what extent genetic ever, whether PDs should be conceptualized dimen- risk factors are shared between PDs, or between PDs sionally or as discrete categories. There seems to be a and axis I disorders. Molecular genetic studies that aim general agreement that PDs are best classified dimen- to identify gene variants associated with PDs will then sionally,16-18and several alternative systems are discussed be reviewed. It is likely that PDs, like most other psy- for DSM-V (see ref 19). chiatric disorders, are etiologically complex, ie, that they are influenced by a number of genetic and environmen- Basic quantitative studies tal risk factors. Studies examining the interplay between genes and the environment will be addressed both in In quantitative genetics, which include family, twin, and relation to quantitative and molecular methods. Finally, adoption studies, the degree to which individual liability future directions will be discussed. to a disorder results from familial effects (in family stud- ies) or genetic and environmental factors (in twin and The classification of personality disorders adoption studies) is estimated. Twin studies have been most commonly used to examine the effects of genetic A PD is defined by DSM-IV as an enduring pattern of risk factors on mental disorders, including PDs, and inner experience and behavior that deviates markedly sophisticated analytical models and statistical tools have from the expectations of the individual's culture, is per- been developed.20,21The proportion of phenotypic dif- vasive and inflexible, has an onset in adolescence or ferences between individuals (or proportion of variance) early adulthood, is stable over time, and leads to distress in a particular population that can be attributed to or impairment.8The DSM-IV classification includes 10 genetic differences is called heritability. In the classical categorical PD diagnoses grouped into three clusters: A twin model the total variance in a phenotype is parti- or the “odd-eccentric,” B or the “dramatic-emotional,” tioned into three variance components, each accounted and C or the “anxious-fearful.”8Cluster A includes para- for by three latent variables: additive genetic, shared noid, schizoid, and schizotypal PD, and Cluster B anti- environment, and individual-specific environment. This social, borderline, histrionic, and narcissistic PD, while implies that the genetic and environmental effects are cluster C includes avoidant, dependent, and obsessive- not directly measured, ie, we do not know which specific compulsive PD. Appendix B includes two additional dis- genes or environmental factors influencing the pheno- orders: depressive and passive-aggressive PDs. type. Genetic effects are usually additive, meaning that Although the classification of PDs in DSM-IV is more the independent effects of different alleles or loci act in empirically based than in former versions, there are sev- an additive way to increase risk for the disorder or trait, eral controversial issues that are unresolved. Substantial but they can also be nonadditive, which means that dif- co-occurrence between the DSM PDs has consistently ferent alleles or loci interact with other alleles or loci been found in both clinical9and community samples.10,11 (epistasis) or different alleles in the same locus (domi- The majority of individuals with a PD receive more than nance). Shared environment includes all environmental one PD diagnosis, and this high degree of overlap seri- exposures that contribute to making twins similar, and ously challenges the descriptive validity of the PD clas- individual-specific or unique environment includes all sification. Comorbidity with Axis I disorders is also environmental exposures that make them different, plus extensive, and results from both clinical and population- measurement error. based studies indicate that the key features in the DSM- Modern twin studies are based on the liability-threshold IV definition (stability over time and early age of onset) model,22which assumes that a large number of genetic do not distinguish PDs from axis I disorders.12 The and environmental risk factors with small individual underlying validity of the DSM axis I - axis II division effects are involved, resulting in a distribution of liabil- has therefore been questioned (eg, refs 12-14). The ity or risk in the population that approximates normal- higher order clustering system has serious limitations, ity. A dichotomous disorder will appear when a certain and has not been consistently validated,8and factor ana- threshold is exceeded. Twin studies can be used regard- lytic studies often do not find support for this three-fac- less of whether PDs are defined categorically or dimen- 104 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 105 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 sionally, but the statistical power is higher if the pheno- the heritability estimates. Although the inter-rater relia- type is ordinal or continuous.23 bility in Kendler et al’s abovementioned study was excel- lent, the test-retest reliability or stability of measurement Normal and abnormal personality traits for PDs has been shown to be imperfect.36It is also likely that genetic and environmental risk factors assessed by Normal personality traits have repeatedly been shown to self-report questionnaires vs interviews are different. A be influenced by genetic factors with heritability estimates second study from the same sample was therefore under- ranging from approximately 30% to 60%.24,25The genetic taken.37Data from a previous self-report questionnaire effects are mainly additive, but nonadditive contributions study were used in addition to the abovementioned inter- of a smaller magnitude have been identified in studies view data to account for unreliability of measurement by with sufficient statistical power.24Shared environmental using two measures differing in both time and mode of factors are usually found to be of minor on no impor- assessment. The estimated heritabilities were substantially tance.24Similar heritability estimates have been found for higher than in the first study: 66% for paranoid, 55% to a dimensional classification of personality disorders based 59% for schizoid, and 72% for schizotypal PD. on self-report.26Numerous studies have shown relatively high correlations between DSM PDs and normal person- Cluster B ality traits of the five-factor model, which includes five broad bipolar domains of extraversion (vs introversion), Antisocial PD-like measures have been extensively stud- agreeableness (vs antagonism) conscientiousness (vs ied using genetic epidemiological methods. In a meta- impulsivity), neuroticism (vs emotional stability), and analysis of 51 twin and adoption studies on antisocial openness (vs closedness to experience),27 but the extent to behavior based largely on records, self-report, and fam- which this is due to genetic factors is not known. ily report, Rhee & Waldman38found that the variance could most parsimoniously be explained by additive DSM personality disorders genetic factors (32%), nonadditive genetic factors (9%), shared environmental factors (16%) and individual-spe- Cluster A cific environmental factors (43%). There were no sig- nificant differences in the magnitude of genetic and envi- Prior studies have suggested that familial/genetic factors ronmental influences for males and females. contribute to the etiology of the three PDs making up the In a review of family studies on borderline PD, White et DSM Cluster A.28A series of twin studies that examine al39found the disorder to aggregate in families. However, various measures of schizoid, schizotypal, and paranoid- significant methodological problems made the results like traits using self-report questionnaires have nearly uni- uncertain. Distel et al estimated that additive genetic fac- formly found significant heritability for these traits and tors explained 42% of the variance in borderline PD fea- failed to find shared environmental effects (eg, refs 29-33). tures assessed by self-report questionnaire, using data from Heritabilities are typically in the range of 35% to 60%. In three countries.40Non-shared environment accounted for a twin study using structured interview data, but based on the rest. In a subsequent extended twin-family study by the a clinical sample, Torgersen et al34found lower heritabil- same group the heritability of borderline PD features was ity estimates for paranoid PD (28%) and schizoid PD found to be 45%, but the genetic effects were both addi- (29%), but much higher heritability for schizotypal PD tive (21%) and dominant (24%).41Nonadditive effects are (61%). The method of ascertainment and the relatively difficult to detect using the classical twin model due to lack low number of participants make the estimates from this of statistical power.23 However, such effects have been study uncertain. In a more recent population-based study found for normal personality traits in twin-sibling studies of dimensional representations of the DSM-IV cluster A with large samples.42 PDs based on structured interviews, Kendler et al35esti- Results from a twin study based on structured interviews mated heritability to be 21% for paranoid, 28% for in a clinical sample suggest that heritability estimates for schizotypal, and 26% for schizoid PD. No shared envi- borderline, histrionic, and narcissistic PD were high, 69%, ronmental effects or sex differences were found. 63%, and 77% respectively.34 More recently, however, In twin studies unreliability of measurement will decrease Torgersen et al43conducted a population-based twin study 105 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 106 C l i n i c a l r e s e a r c h of dimensional representations of the DSM-IV cluster B Disorders in Appendix B PDs. Heritability was estimated to be 38% for antisocial PD, 31% for histrionic PD, 24% for narcissistic PD and In a population-based twin study of depressive PD, 35% for borderline PD. No shared environmental influ- Ørstavik et al46 found that liability could best be ences or sex or effects were found. explained by additive genetic and unique environmen- tal factors alone, with heritability estimates of 49% in Cluster C females and 25% in males. Unlike the results for the other DSM-IV PDs, both quantitative and qualitative A family study of the anxious-fearful cluster indicated sig- sex-differences were found corresponding to findings nificant familiality for DSM-III avoidant and dependent from studies on major depression.47Significant familial PD,44and in a clinically based twin study, heritability esti- aggregation has also been found for DSM-IV passive mates for avoidant, dependent, and obsessive-compulsive aggressive PD.48 PD were found to be 28%, 57%, and 77%, respectively.34 Results from a population-based study of dimensional Multivariate studies representations of DSM-IV Cluster C PDs,45 however, indicated that heritability estimates were similar for If heritability has been established, several more com- avoidant PD (35%), but lower for dependent (31%) and plex models can be employed to explore the nature and for obsessive-compulsive PD (27%), again illustrating the mode of action of the genetic risk factors.7Multivariate importance of method of ascertainment. This discrepancy analyses, which comprise models where several pheno- is probably in part due to difference in methods of ascer- types are included and different structures of the latent tainment. No shared environmental effects or sex differ- factors can be specified,20 can be used to estimate to ences have been found for cluster C PDs. what extent genetic and environmental risk factors are .28 .34 .31 .00 .24 .00 .33 .00 .37 .41 Figure 1. Genetic parameter estimates from best fitting model for ten DSM-IV personality disorders. Path estimates are standardized regression coef- ficients, so they must be squared to equal the proportion of variance accounted for in the dependent variable. A stands for additive genetic effects. The subscripts C and S stand, respectively, for common factor and disorder-specific effects. The first, second and third genetic com- mon factors are indicated by the subscripts , and . Paths with values ≥ +0.28 (which account for ≥ 8% of phenotypic variance) are col- C1 C2 C3 ored with the first, second, and third common factor indicated by, respectively, red, green, and blue and the disorder-specific factors by magenta. Paths not exceeding the + 0.28 cutoff are depicted in gray. From ref 52: Kendler KS, Aggen SH, Czajkowski N, et al. The structure of genetic and environmental risk factors for DSM-IV personality disorders a multivariate twin study. Arch Gen Psychiatry. 2008;65:1438-1446. Copyright © American Medical Association 2008 106 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 107 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 specific to a given PD or shared in common with other The results are also to a large extent consistent with a PDs or axis I disorders, and thus to investigate sources prior multivariate twin study of the dimensional classi- of comorbididity.49,50By including measures of the same fication system of personality disorder trait mentioned phenotypes on different points in time, they can also be above26in which Livesley et al identified four genetic used to determine if genetic effects differ over time in factors loading on four phenotypic dimensions called a developmental perspective. “emotional dysregulation,” “dissocial behavior,” “inhi- bition,” and “compulsivity.” DSM-IV personality disorders Taken together these results indicate that genetic risk factors for DSM-IV PDs do not reflect the cluster A, B, Cluster A PDs have been found to aggregate in families and C typology. However, this is well reflected in the of probands with schizophrenia (see below). Familial structure of the environmental risk factors, suggesting coaggregation has also been found for borderline PD and that the comorbidity of PDs within clusters is due to antisocial PD39and for borderline PD and all the other environmental experiences. cluster B PDs,51 as well as for the DSM-III cluster C PDs.44A population-based twin study including all PDs Personality disorders and Axis I disorders within cluster B indicated that borderline PD and anti- social PD appeared to share genetic risk factors above Several lines of evidence indicate specific axis I/axis II and beyond those shared in common with the other clus- relationships,54,55suggesting that common genetic or envi- ter B disorders,43and a twin study of cluster C PDs sug- ronmental liability factors might predispose to several gested that genetic factors influencing obsessive-com- disorders within clusters that transcend the axis I/axis II pulsive PD appeared to be relative specific to this division.13,49,56 disorder.45Kendler et al, in the only population-based multivariate twin study including all 10 DSM-IV PDs Schizophrenia that has been published,52 found that the best-fitting model included three genetic and three environmental A number of family and adoption studies have exam- factors in addition to disorder-specific factors. The struc- ined the risk for paranoid, schizoid, and schizotypal PDs ture of the genetic factors is shown in Figure 1. The first in relatives of schizophrenic and control probands. While genetic factor (A ) had high loadings on PDs from all 3 a few studies can be found where all threecluster A PDs C1 clusters including paranoid, histrionic, borderline, narcis- are at increased risk in relatives of schizophrenic sistic, dependent, and obsessive-compulsive PD. This fac- probands,57,58 more common are studies that find that tor probably reflects a broad vulnerability to PD pathol- only schizotypal PD59-63or schizotypal PD and paranoid ogy and/or negative emotionality, and is related to PD64have a significant familial relationship with schizo- genetic liability to the normal personality trait neuroti- phrenia. Taken together, these results suggest that cism. The second genetic factor (A )was quite specific schizotypal PD has the closest familial relationship to C2 with substantial loadings only on borderline and antiso- schizophrenia, followed by paranoid and schizoid PD, cial PD. This is consistent with the results from the above- and are consistent with the hypothesis that a common mentioned family studies,39and suggests genetic liability genetic risk factor for cluster A PDs reflects—in the gen- to a broad phenotype for impulsive/aggressive behavior. eral population—the liability to schizophrenia.35 The The third factor identified (A )had high loadings only extended phenotype believed to reflect this genetic lia- C3 on schizoid and avoidant PD. This can be interpreted in bility to schizophrenia is often described by the term several ways. It might in part reflect genetic risk for schiz- schizophrenia spectrum. Schizotypal PD has been sug- ophrenia spectrum pathology (see below). From the per- gested to be the prototypical disorder in this spectrum.65 spective of the five-factor model of normal personality it In a recent family study, Fogelson et al66 showed that reflects genetic liability for introversion.53 Finally, it is avoidant PD, currently classified in DSM cluster C, also noteworthy that obsessive-compulsive PD had the high- occurred more frequently in relatives of probands with est disorder-specific genetic loading, which parallels prior schizophrenia even after controlling for schizotypal and findings that this PD shares little genetic and environ- paranoid PD. This replicates findings from earlier stud- mental liability with the other cluster C PDs. ies,58,67 and suggest that avoidant PD should also be 107 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 108 C l i n i c a l r e s e a r c h included in this spectrum. It is also in part in accordance substance-use disorders (often called externalizing dis- with the results from the multivariate study by Kendler orders) share a common genetic liability (eg, refs 68,74). et al described above,52where avoidant and schizoid PD In a family-twin study, Hicks et al75found that a highly share genetic liability. heritable (80%) general vulnerability to all the exter- nalizing disorders accounted for most of the familial Internalizing disorders resemblance. Disorder-specific vulnerabilities were detected for conduct disorder, alcohol dependence, and Mood and anxiety disorders (often called internalizing drug dependence, but not for antisocial PD. The same disorders) share genetic and environmental liability fac- group also reported an association between externaliz- tors with each other,68and with the normal personality ing disorders and reduced amplitude of the P3 compo- trait neuroticism,69which correlates strongly with several nent of the brain event-related potential, suggesting that PDs, especially in cluster B and C.53 this could be a common biological marker for the bio- Family studies indicate that borderline PD and major logical vulnerability to these disorders.76 depression share familial risk factors.51,70In a population- based multivariate twin study of major depression and Longitudinal studies DSM-IV PDs, Reichborn-Kjennerud et al71 found that dimensional representations of borderline PD from clus- Most of the genetic studies that have investigated ter B, avoidant PD from cluster C, and paranoid PD from changes in genetic influences on PDs over time have cluster A were all independently and significantly associ- used measures related to antisocial PD. The following ated with increased risk for major depression. Multivariate examples illustrate the potential of longitudinal quan- twin modeling indicated that one latent factor accounted titative genetic methods. In a twin study, Lyons et al77 for the genetic covariance between major depression and demonstrated that the genetic influence on symptoms of the three PDs. The genetic correlations between major DSM-III-R antisocial PD was much more prominent in depression and borderline, avoidant, and paranoid PD adulthood than in adolescence. Silberg et al78studying were respectively +0.56, +0.22, and +0.40. No sex differ- twins between 10 and 17 years of age found a single ences or shared environmental effects were found. These genetic factor that influenced antisocial behavior begin- results indicate that vulnerability to general PD pathology ning at age 10 through young adulthood, a shared envi- and major depression are closely related. In a bivariate ronmental effect beginning in adolescence, a transient twin study, Ørstavik et al72found that a substantial part of genetic effect at puberty and genetic influences specific the covariation between major depressive disorder and to adult antisocial behavior. In another recent twin study depressive PD was accounted for by genetic factors with of externalizing disorders, biometric analyses revealed a genetic correlation of 0.56. Results from another popu- increasing genetic variation and heritability for men but lation-based twin study, investigating the sources of co- a trend toward decreasing genetic variation and increas- occurrence between social phobia and of avoidant PD in ing environmental effects for women.79 females, indicated that social phobia and avoidant PD were influenced by identical genetic factors, whereas the Gene-environment interplay environmental factors influencing the two disorders were uncorrelated.73This suggests that an individual with high In the traditional models of disease etiology in psychiatric genetic liability will develop avoidant PD versus social epidemiology the causal pathway is conceptualized as phobia entirely as a result of environmental risk factors moving from the environment to the organism. However, unique to each disorder, which is in accordance with the since genes influence behavior, genetic factors can indi- hypothesis of underlying psychobiological dimensions cut- rectly influence or control exposure to the environment,20 ting across the axis I/ axis II classification system. called gene-environment correlation.20,80,81Genetic factors can also control an individual’s sensitivity to the environ- Substance-use disorders ment, ie, genetic factors influence or alter an organism’s response to environmental stressors.20,80,81This is usually Numerous family, adoption and twin studies have called gene-environment interaction. In quantitative stud- demonstrated that antisocial PD, conduct disorder, and ies of gene-environment interplay, genetic factors are 108 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 109 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 either inferred (eg, disorder in biological parent in adop- Molecular genetic studies tion studies) or modeled as a latent variable.80,82 Twin and adoption studies have provided much of the Traditionally, linkage and association studies have been evidence for gene-environment correlations by demon- most commonly used for mapping disease loci.94Most of strating genetic influences for a number of measures of the molecular genetic studies of PDs has been done the environment.80Overall, the evidence from twin and using hypothesis-driven candidate gene association stud- adoption studies suggests that gene-environment corre- ies95focusing on particular genes related to the neuro- lations are mediated by heritable personality traits and transmitter pathways, especially in the serotonergic and possibly PDs.81,83,84 dopaminergic systems. Although the number of genetic The initial indications that gene-environment interac- association studies are increasing exponentially, only a tion was likely to be operating came from adoption and very small fraction of positive results are replicated.96,97 twin studies.85 Gene-environment interaction was Until further replications are published the results demonstrated in an adoption study as early as in 1974, reviewed below must therefore be considered tentative. when Crowe86found that early institutional care was a risk factor for later antisocial behavior only when a Cluster A genetic risk factor was present. In another adoption study, Cadoret et al87 found significant gene-environ- Consistent with the hypothesis that schizophrenia and ment interaction by showing that there was a negligible related PDs are linked to dopaminergic dysfunction, risk for antisocial behavior from a genetic risk alone Rosmond et al98found that Cluster A PDs were associ- (antisocial behavior in the biological parent), no effect ated with a polymorphism in the gene coding for the of an adverse adoptive family environment alone, but a dopamine 2 receptor (DRD2). Building on results from substantial effect when both were present. The finding quantitative genetic studies indicating that common was replicated in a later study with a larger number of genetic risk factors exist for schizotypal PD and schizo- adoptees,88Jaffe et al,89using a twin design, found sig- phrenia, Stefanis et al99examined the potential impact nificant gene-environment interaction with respect to of SNPs within the four most prominent candidate genes childhood maltreatment and the development of anti- for schizophrenia. Dysbindin (DTNBP1) and D-amino- social behavior, and in a twin study Tuvblad et al90 acid oxidase (DAAO) both showed associations with demonstrated a significant gene-environment interac- symptoms of schizotypy. Similarly, Fanous et al100using a tion by showing that the heritability for adolescent anti- linkage approach, found that a subset of schizophrenia social behavior is higher in socioeconomic advantaged susceptibility genes also affect schizotypy in nonpsy- environments. Using an advanced family design, chotic relatives. Significant associations with schizotypal Feinberg et al91recently found an interaction of geno- personality traits have also been found in several stud- type and both parental negativity and low warmth pre- ies with polymorphisms in the gene coding for catechol- dicting antisocial behavior. Significant gene-environ- O-methyltransferase (COMT)100,102,103an enzyme involved ment interaction has also been demonstrated in in the degradation of catecholamines, and linked to the schizophrenia spectrum disorders. In an adoption study etiology of schizophrenia.104 Tienari et al92showed that there was a significant asso- ciation between disordered rearing and the diagnosis of Cluster B schizophrenia spectrum disorder in the offspring of mothers with but not in offspring of mothers without Multiple lines of evidence suggest that dysfunction in the the diagnoses. In a community based twin study, Hicks serotonin (5-HT) system is associated with impulsivity, et al demonstrated a significant gene-environment aggression, affective lability, and suicide. Genes linked interaction with a number of environmental risk factors to the function of this neurotransmitter can therefore be showing that greater environmental adversity was asso- considered possible candidate genes for borderline and ciated with increased genetic risk for antisocial PD and antisocial PD. Kennedy and coworkers found that bor- substance use disorders.93Significant gene-environment derline PD was associated with polymorphisms in the interaction has also been demonstrated in quantitative serotonin transporter gene (5-HTTLPR),105and poly- studies of anxiety and mood disorders.81 morphisms in the gene coding for the catabolic enzyme 109 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 110 C l i n i c a l r e s e a r c h monoamine oxidase A (MAOA), involved in the regu- authors to conclude that DRD3 may contribute to the lation of biogenic amines like serotonin, norepinephrine, development of obsessive-compulsive PD.121 and dopamine,106 but not polymorphisms in the gene coding for the serotonin 5-HT2A receptor.107Recently Gene-environment interplay the group has conducted a gene-gene interaction study with a number of polymorphisms in seven serotonin Few studies of gene-environment correlation using mea- genes (including the three mentioned above), conclud- sured genes and measured environments have been pub- ing that “serotonin genes and their interaction may play lished. Dick et al121found that individuals who had a poly- a role in the susceptibility to borderline PD.”108Other morphism in a gene (GABRA2) associated with alcohol groups have reported similar findings. A main effect of dependence were less likely to be married, in part because the 5-HTTLPR polymorphism on borderline PD has they were at higher risk for antisocial PD and were less been found in bulimic women,109and Lyons-Ruth et al likely to be motivated by a desire to please others. Other found a significant relationship between the short results confirm the existence of gene-environment corre- 5HTTLPR allele and both borderline and antisocial lation with measured genes in both the dopaminergic and PD,110but other studies have failed to find an association serotonergic system, and provide preliminary support for between this polymorphism and cluster B PDs.111 the finding that correlations are mediated by behavioral Polymorphisms in the MAOA gene have been found to and personality characteristics.84 be associated with cluster B PDs,112 and antisocial Gene-environment interaction studies using identified traits.113 Tryptophan hydroxylase is the rate-limiting susceptibility genes rather than unmeasured latent enzyme in the serotonin metabolic pathway. Two genes genetic factors can provide more secure estimates.84 related to this enzyme, the tryptophan hydroxylase 1 and Based on results from quantitative genetic studies show- 2 genes (TPH1and TPH2), have been associated with ing gene-environment interaction for antisocial behav- borderline PD114and personality traits related to emo- ior, Caspi et al123studied the association between child- tional instability, as well as to cluster B and cluster C hood maltreatment, and a functional polymorphism in PDs.115Taken together, these findings suggest that bor- the promoter region of the MAOA gene on antisocial derline and antisocial PD and possibly also the other behavior assessed through a range of categorical and cluster B PDs, are influenced by genes regulating the dimensional measures using questionnaire and interview serotonergic system. They are also consistent with the data plus official records. The results showed no main finding of shared genetic influence on borderline PD effect of the gene, a main effect for maltreatment and a and antisocial PD, and on borderline PD and the other substantial and significant interaction between the gene cluster B PDs found in multivariate twin studies.43,52 and adversity. The maltreated children whose genotype conferred low levels of MAOA expression more often Cluster C developed conduct disorder and antisocial personality than children with a high activity MAOA genotype. It has previously been suggested that the 5-HTTLPR Foley et al124replicated this finding and extended the ini- polymorphism was associated with anxiety-related tial analysis by showing that the gene-environment inter- traits,116but later studies have yielded conflicting results action could not be accounted for by gene-environment (see ref 117). Patients diagnosed with cluster C PDs, correlation. Other studies have failed to replicate the have not been found to be significantly higher in the fre- gene-environment interaction effect (eg, ref 125). In a quency of the short form allele of the 5- recent meta-analysis, however, the original finding was HTTLPR.111Recent results, on the other hand, indicate replicated. In addition the findings was extended to that variations in the COMT gene contribute to genetic include childhood (closer in time to the maltreatment), risk shared across a range of anxiety-related pheno- and the possibility of a spurious finding was ruled out by types.118,119Joyce120found an association between avoidant accounting for gene-environment correlation.126 The and obsessive-compulsive PD symptoms and the interaction between MAOA and childhood maltreat- dopamine D3 receptor (DRD3) polymorphism. In a ment in the etiology of antisocial PD appear to be one later study and a meta-analysis, the finding for obsessive- of the few replicated findings in the molecular genetics compulsive symptoms were replicated, leading the of PDs. 110 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 111 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 Future directions Methods like genome-wide association studies,128 analyses of copy-number variation,129studies of rare Information from genetic epidemiologic studies can con- genetic variants,130 epigenetic methods,131 and deep tribute to improvement in the validity of diagnoses of men- sequencing of genomic regions132 have not yet been tal disorders, and thereby a more empirically based classifi- applied to PDs, and will hopefully contribute to our cation system.49,56,127 Several lines of evidence, including understanding of the genetic etiology of these disor- multivariate twin studies, have shown that common axis I ders in the future. One problem is, however, that the disorders can be divided into two main groups (internalizing current phenotypes might be inadequate.128It is highly and externalizing) based on shared etiological factors.49,68 unlikely that the new DSM-V classification of PDs will Currently an alternative classification system are being con- provide a solution. A strategy that has been proposed sidered for DSM-V based on the hypothesis that, in addition to increase the rate of success for molecular genetics to phenotypic similarity, spectra or clusters of disorder can in psychiatry is the use of endophenotypes, defined as be identified based on shared liability or risk factors.56Such a heritable characteristic that is along the pathway clusters transcend the axis I-axis II division. Multivariate twin between a disorder and genotype.5Although the strat- studies, including a comprehensive number of axis I and axis egy has not yet proven to be successful,133it has been II disorders, could provide new important insights relevant suggested that this approach should be applied to the to this proposal and further clarify the etiology of mental dis- study of PDs by using clinical dimensions like for orders by identifying genetic and environmental risk factors example affective instability, impulsivity, and aggres- shared in common between groups of disorders. sion instead of diagnoses.134 ❏ REFERENCES 15. Sheets E, Craighead WE. Toward an empirically based classification of personality pathology. Clinl Psychol Sci Pract. 2007;14:77-93. 1. American Psychiatric Association. Diagnostic and Statistical Manual of 16. Oldham JM, Skodol AE. Charting the future of axis II. J Personal Disord. Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 2000;14:17-29. 1980. 17. Widiger TA, Samuel DB. Diagnostic categories or dimensions? A ques- 2. McGuffin P, Moffitt T, Thapar A. Personality disorders. In: McGuffin P, tion for the Diagnostic and Statistical Manual of Mental Disorders - Fifth Owen MJ, Gottesman II, eds. Psychiatric Genetics and Genomics. Oxford, UK: Edition. J Abnorm Psychol. 2005;114:494-504. Oxford University Press; 2002:183-210. 18. Widiger TA, Trull TJ. Plate tectonics in the classification of personality 3. Livesley WJ, Jang KL. The Behavioral genetics of personality disorder. disorder - shifting to a dimensional model. Am Psychologist. 2007;62:71-83. Ann Rev Clin Psychol. 2008;4247-274. 19. Krueger RF, Skodol AE, Livesley WJ, Shrout PE, Huang YQ. Synthesizing 4. Reichborn-Kjennerud T. Genetics of personality disorders. Psychiatr Clin dimensional and categorical approaches to personality disorders: refining N Am. 2008;31:421-440. the research agenda for DSM-V Axis II. Int J Methods Psych Res. 2007;16:S65- 5. Gottesman II, Gould TD. The endophenotype concept in psychiatry: ety- S73. mology and strategic intentions. Am J Psychiatry. 2003;160:636-645. 20. Kendler KS. Twin studies of psychiatric illness: an update. Arch Gen 6. Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizo- Psychiatry. 2001;58:1005-1014. phrenia: an overview of the use of endophenotypes in order to understand 21. Neale MC, Boker SM, Xie G, Maes HH. Mx Statistical Modeling. 5th. a complex disorder. Schizophr Bull. 2007;33:21-32. 1999. Box 710 MCV, Richmond, VA 23298: Medical College of VA of VA 7. Kendler KS. Psychiatric genetics: a methodologic critique. Am J Commonwealth Univ. Ref Type: Computer Program. Psychiatry. 2005;162:3-11. 22. Falconer DS. The inheritance of liability to certain diseases, estimated 8. American Psychiatric Association. Diagnostic and Statistical Manual of from the incidence among relatives. Ann Hum Genet. 1965;29:51-76. Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 23. Neale MC, Eaves LJ, Kendler KS. The power of the classical twin study 1994. to resolve variation in threshold traits. Behav Genet. 1994;24:239-258. 9. Oldham JM, Skodol AE, Kellman HD, Hyler SE, Rosnick L, Davies M. 24. Bouchard TJ, Loehlin JC. Genes, evolution, and personality. Behav Genet. Diagnosis of DSM-III-R personality disorders by two structured interviews: 2001;31:243-273. patterns of comorbidity. Am J Psychiatry. 1992;149:213-220. 25. Ando J, Suzuki A, Yamagata S, et al. Genetic and environmental struc- 10. Coid J, Yang M, Tyrer P, Roberts A, Ullrich S. Prevalence and correlates ture of Cloninger's temperament and character dimensions. J Personal Disord. of personality disorder in Great Britain. Br J Psychiatry. 2006;188:423-431. 2004;18:379-393. 11. Lenzenweger MF, Lane MC, Loranger AW, Kessler RC. DSM-IV person- 26. Livesley WJ, Jang KL, Vernon PA. Phenotypic and genetic structure of ality disorders in the national comorbidity survey replication. Biol Psychiatry. traits delineating personality disorder. Arch Gen Psychiatry. 1998;55:941-948. 2007;62:553-564. 27. Saulsman LM, Page AC. The five-factor model and personality disorder 12. Krueger RF. Continuity of axes I and II: toward a unified model of per- empirical literature: a meta-analytic review. Clin Psychol Rev. 2004;23:1055- sonality, personality disorders, and clinical disorders. J Personality Disord. 1085. 2005;19:233-261. 28. Parnas J, Licht D, Bovet P. Cluster A personality disorders: a review. In: 13. Siever LJ, Davis KL. A psychobiological perspective on the personality Maj M, Akiskal H, Mezzich JE, Okasha A, eds. Personality Disorders. New York, disorders. Am J Psychiatry. 1991;148:1647-1658. NY: John Wiley & Sons Ltd; 2005:1-124. 14. Widiger TA. Personality disorder and Axis I psychopathology: the prob- 29. Kendler KS, Heath A, Martin NG. A genetic epidemiologic study of self- lematic boundary of Axis I and axis II. J Personality Disord. 2003;17:90-108. report suspiciousness. Comp Psychiatry. 1987;28:187-196. 111 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 112 C l i n i c a l r e s e a r c h La epidemiología genética de los trastornos Epidémiologie génétique des troubles de la de personalidad personnalité Los estudios de epidemiología genética señalan que Des études d’épidémiologie génétique montrent los diez trastornos de personalidad (TP) clasificados que les 10 troubles de la personnalité (TP) classés en el eje II del DSM-IV tienen una herencia leve a sur l’axe II du DSM-IV sont légèrement à modéré- moderada. Los factores ambientales compartidos y ment transmissibles. Les facteurs génétiques non genéticos no aditivos son de importancia menor o additifs et les facteurs environnementaux partagés carecen de ésta. No se han identificado diferencias sont de peu ou sans importance et il n’y a pas de por sexo. Los estudios multivariados sugieren que différences selon le sexe. Des études multivariées la amplia comorbilidad entre los TP se puede expli- suggèrent que trois facteurs de risque génétiques car por tres factores de riesgo ambientales y gené- et environnementaux courants peuvent expliquer ticos comunes. Los factores genéticos no reflejan la la comorbidité importante entre les TP. Les facteurs estructura de grupos del DSM-IV, pero sí: 1) la alta génétiques ne reflètent pas la structure en cluster vulnerabilidad para la patología de los TP o para la du DSM-IV mais plutôt : 1) une grande vulnérabilité emocionalidad negativa, 2) la alta impulsividad/baja aux TP ou à une émotivité négative ; 2) une impul- afabilidad y 3) la introversión. Los factores de riesgo sivité importante/peu d’amabilité ; 3) une introver- genéticos y ambientales comunes contribuyen a la sion. Des facteurs de susceptibilité génétiques et comorbilidad entre parejas o grupos de trastornos environnementaux communs participent à la de los ejes I y II. Los estudios de genética molecular comorbidité entre les paires ou les groupes des de los TP, principalmente los estudios de asociación troubles de l’axe I et de l’axe II. Des études de géné- de genes candidatos, señalan que están involucra- tique moléculaire des TP, pour la plupart des études dos los genes vinculados a los sistemas de neuro- d’association de gène candidat, montrent que sont transmisión, principalmente serotoninérgicos y impliqués les gènes liés aux voies des neurotrans- dopaminérgicos. Estudios a futuro, que utilicen metteurs, surtout dans les systèmes sérotoniner- métodos más nuevos como la asociación del giques et dopaminergiques. Des études futures, uti- genoma completo, pueden aprovechar el empleo lisant la méthodologie de recherche d'associations de endofenotipos. sur génome entiers pourraient bénéficier de l'utili- sation d' endophénotypes. 30. Claridge G, Hewitt JK. A Biometrical study of schizotypy in a normal 38. Rhee SH, Waldman ID. Genetic and environmental influences on anti- population. Person Individ Diff.1987;8:303-312. social behavior: a meta-analysis of twin and adoption studies. Psychol Bull. 31. Kendler KS, Hewitt JK. The structure of self-report schizotypy in twins. 2002;128:490-529. J Personal Disord. 1992;61-17. 39. White CN, Gunderson JG, Zanarini MC, Hudson JI. Family studies of bor- 32. Linney YM, Murray RM, Peters ER, Macdonald AM, Rijsdijk F, Sham PC. derline personality disorder: A review. Harv Rev Psychiatry. 2003;11:8-19. A quantitative genetic analysis of schizotypal personality traits. Psychol Med. 40. Distel MA, Trull TJ, Derom CA, et al. Heritability of borderline personality 2003;33:803-816. disorder features is similar across three countries. Psychol Med. 2008;38:1219-1229. 33. Jang KL, Woodward TS, Lang D, Honer WG, Livesley WJ. The genetic 41. Distel MA, Rebollo-Mesa I, Willemsen G, et al. Familial resemblance of and environmental basis of the relationship between schizotypy and per- borderline personality disorder features: genetic or cultural transmission? sonality - a twin study. J Nerv Ment Dis. 2005;193:153-159. Plos One. 2009;4:e5334. 34. Torgersen S, Lygren S, Oien PA, et al. A twin study of personality dis- 42. Keller MC, Coventry WL, Heath AC, Martin NG. Widespread evidence orders. Comp Psychiatry. 2000;41:416-425. for non-additive genetic variation in Cloninger's and Eysenck's personality 35. Kendler KS, Czajkowski N, Tambs K, et al. Dimensional representations dimensions using a twin plus sibling design. Behav Genet. 2005;35:707-721. of DSM-IV Cluster A personality disorders in a population-based sample of 43. Torgersen S, Czajkowski N, Jacobson K, et al. Dimensional representa- Norwegian twins: a multivariate study. Psychol Med. 2006;36:1583-1591. tions of DSM-IV cluster B personality disorders in a population-based sample 36. McGlashan TH, Grilo CM, Sanislow CA, et al. Two-year prevalence and of Norwegian twins: a multivariate study. Psychol Med. 2008;38:1617-1625. stability of individual DSM-IV criteria for schizotypal, borderline, avoidant, 44. Reich JH. Familiality of DSM-III dramatic and anxious personality clus- and obsessive-compulsive personality disorders: toward a hybrid model of ters. J Nerv Ment Dis. 1989;177:96-100. axis II disorders. Am J Psychiatry. 2005;162:883-889. 45. Reichborn-Kjennerud T, Czajkowski N, Neale MC, et al. Genetic and 37. Kendler KS, Myers J, Torgersen S, Neale MC, Reichborn-Kjennerud T. environmental influences on dimensional representations of DSM-IV clus- The heritability of cluster A personality disorders assessed by both personal ter C personality disorders: a population-based multivariate twin study. interview and questionnaire. Psychol Med. 2007;37:655-665. Psychol Med. 2007;37:645-653. 112

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DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 103 C l i n i c a l r e s e a r c h The genetic epidemiology of personality disorders Ted Reichborn-Kjennerud, MD, PhD T he introduction of personality disorders (PDs) as diagnostic categories on a separate axis (Axis II) in the third edition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-III) in 19801had a dramatic effect on the level of interest in these disorders among researchers, and the number of published articles increased substantially. However, the number of genetic epidemiologic studies of the DSM PDs has remained limited compared with studies on both clinical disorders like schizophrenia, depression, and anxiety disorders (which are classified on Axis I in DSM), and on normal Genetic epidemiologic studies indicate that all ten per- personality traits.2-4 sonality disorders (PDs) classified on the DSM-IV axis II The understanding of the role of genetic factors in the are modestly to moderately heritable. Shared environ- etiology of disorders and traits is inseparably linked to mental and nonadditive genetic factors are of minor or classification, since a precise definition of the phenotype no importance. No sex differences have been identified. is a prerequisite for all successful genetic studies. In this Multivariate studies suggest that the extensive comor- review we will focus on PDs as they are classified in the bidity between the PDs can be explained by three com- DSM; a system that serves many purposes, and is not mon genetic and environmental risk factors. The genetic specifically designed for genetic studies. This is a prob- factors do not reflect the DSM-IV cluster structure, but lem not only for the genetics of PDs, and the search for rather: i) broad vulnerability to PD pathology or nega- better phenotypes for genetic studies of mental disorders tive emotionality; ii) high impulsivity/low agreeableness; is especially well illustrated in the literature on schizo- and iii) introversion. Common genetic and environmen- phrenia (eg, refs 5, 6). tal liability factors contribute to comorbidity between The goal of psychiatric genetic epidemiology is to under- pairs or clusters of axis I and axis II disorders. Molecular stand the role of genetic and environmental factors in genetic studies of PDs, mostly candidate gene association the etiology of mental disorders.7In this paper we will studies, indicate that genes linked to neurotransmitter focus mainly on the genetic factors. After a brief outline pathways, especially in the serotonergic and dopamin- of the current DSM axis II PD classification, we will ergic systems, are involved. Future studies, using newer methods like genome-wide association, might take Author affiliations: Division of Mental Health, Norwegian Institute of advantage of the use of endophenotypes. Public Health Institute of Psychiatry, University of Oslo, Norway; Department of Epidemiology, Columbia University, New York, NY, USA © 2010, LLS SAS Dialogues Clin Neurosci.2010;12:103-114. Address for correspondence:Ted Reichborn-Kjennerud, Director, Department of Keywords:personality disorder; axis I disorder; genetics; twin study; molecular Adult Mental Health, Norwegian Institute of Public Health, Box 4404 Nydalen, genetic study; candidate gene N-0403 Oslo, Norway (e-mail: [email protected]) Copyright © 2010 LLS SAS. All rights reserved 103 www.dialogues-cns.org DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 104 C l i n i c a l r e s e a r c h evaluate the evidence for genetic influences on PDs and tor structure.15One of the most controversial and long- examine quantitative genetic studies that explore the standing issues in the field of PD classification is, how- specificity of the genetic effects, ie, to what extent genetic ever, whether PDs should be conceptualized dimen- risk factors are shared between PDs, or between PDs sionally or as discrete categories. There seems to be a and axis I disorders. Molecular genetic studies that aim general agreement that PDs are best classified dimen- to identify gene variants associated with PDs will then sionally,16-18and several alternative systems are discussed be reviewed. It is likely that PDs, like most other psy- for DSM-V (see ref 19). chiatric disorders, are etiologically complex, ie, that they are influenced by a number of genetic and environmen- Basic quantitative studies tal risk factors. Studies examining the interplay between genes and the environment will be addressed both in In quantitative genetics, which include family, twin, and relation to quantitative and molecular methods. Finally, adoption studies, the degree to which individual liability future directions will be discussed. to a disorder results from familial effects (in family stud- ies) or genetic and environmental factors (in twin and The classification of personality disorders adoption studies) is estimated. Twin studies have been most commonly used to examine the effects of genetic A PD is defined by DSM-IV as an enduring pattern of risk factors on mental disorders, including PDs, and inner experience and behavior that deviates markedly sophisticated analytical models and statistical tools have from the expectations of the individual's culture, is per- been developed.20,21The proportion of phenotypic dif- vasive and inflexible, has an onset in adolescence or ferences between individuals (or proportion of variance) early adulthood, is stable over time, and leads to distress in a particular population that can be attributed to or impairment.8The DSM-IV classification includes 10 genetic differences is called heritability. In the classical categorical PD diagnoses grouped into three clusters: A twin model the total variance in a phenotype is parti- or the “odd-eccentric,” B or the “dramatic-emotional,” tioned into three variance components, each accounted and C or the “anxious-fearful.”8Cluster A includes para- for by three latent variables: additive genetic, shared noid, schizoid, and schizotypal PD, and Cluster B anti- environment, and individual-specific environment. This social, borderline, histrionic, and narcissistic PD, while implies that the genetic and environmental effects are cluster C includes avoidant, dependent, and obsessive- not directly measured, ie, we do not know which specific compulsive PD. Appendix B includes two additional dis- genes or environmental factors influencing the pheno- orders: depressive and passive-aggressive PDs. type. Genetic effects are usually additive, meaning that Although the classification of PDs in DSM-IV is more the independent effects of different alleles or loci act in empirically based than in former versions, there are sev- an additive way to increase risk for the disorder or trait, eral controversial issues that are unresolved. Substantial but they can also be nonadditive, which means that dif- co-occurrence between the DSM PDs has consistently ferent alleles or loci interact with other alleles or loci been found in both clinical9and community samples.10,11 (epistasis) or different alleles in the same locus (domi- The majority of individuals with a PD receive more than nance). Shared environment includes all environmental one PD diagnosis, and this high degree of overlap seri- exposures that contribute to making twins similar, and ously challenges the descriptive validity of the PD clas- individual-specific or unique environment includes all sification. Comorbidity with Axis I disorders is also environmental exposures that make them different, plus extensive, and results from both clinical and population- measurement error. based studies indicate that the key features in the DSM- Modern twin studies are based on the liability-threshold IV definition (stability over time and early age of onset) model,22which assumes that a large number of genetic do not distinguish PDs from axis I disorders.12 The and environmental risk factors with small individual underlying validity of the DSM axis I - axis II division effects are involved, resulting in a distribution of liabil- has therefore been questioned (eg, refs 12-14). The ity or risk in the population that approximates normal- higher order clustering system has serious limitations, ity. A dichotomous disorder will appear when a certain and has not been consistently validated,8and factor ana- threshold is exceeded. Twin studies can be used regard- lytic studies often do not find support for this three-fac- less of whether PDs are defined categorically or dimen- 104 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 105 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 sionally, but the statistical power is higher if the pheno- the heritability estimates. Although the inter-rater relia- type is ordinal or continuous.23 bility in Kendler et al’s abovementioned study was excel- lent, the test-retest reliability or stability of measurement Normal and abnormal personality traits for PDs has been shown to be imperfect.36It is also likely that genetic and environmental risk factors assessed by Normal personality traits have repeatedly been shown to self-report questionnaires vs interviews are different. A be influenced by genetic factors with heritability estimates second study from the same sample was therefore under- ranging from approximately 30% to 60%.24,25The genetic taken.37Data from a previous self-report questionnaire effects are mainly additive, but nonadditive contributions study were used in addition to the abovementioned inter- of a smaller magnitude have been identified in studies view data to account for unreliability of measurement by with sufficient statistical power.24Shared environmental using two measures differing in both time and mode of factors are usually found to be of minor on no impor- assessment. The estimated heritabilities were substantially tance.24Similar heritability estimates have been found for higher than in the first study: 66% for paranoid, 55% to a dimensional classification of personality disorders based 59% for schizoid, and 72% for schizotypal PD. on self-report.26Numerous studies have shown relatively high correlations between DSM PDs and normal person- Cluster B ality traits of the five-factor model, which includes five broad bipolar domains of extraversion (vs introversion), Antisocial PD-like measures have been extensively stud- agreeableness (vs antagonism) conscientiousness (vs ied using genetic epidemiological methods. In a meta- impulsivity), neuroticism (vs emotional stability), and analysis of 51 twin and adoption studies on antisocial openness (vs closedness to experience),27 but the extent to behavior based largely on records, self-report, and fam- which this is due to genetic factors is not known. ily report, Rhee & Waldman38found that the variance could most parsimoniously be explained by additive DSM personality disorders genetic factors (32%), nonadditive genetic factors (9%), shared environmental factors (16%) and individual-spe- Cluster A cific environmental factors (43%). There were no sig- nificant differences in the magnitude of genetic and envi- Prior studies have suggested that familial/genetic factors ronmental influences for males and females. contribute to the etiology of the three PDs making up the In a review of family studies on borderline PD, White et DSM Cluster A.28A series of twin studies that examine al39found the disorder to aggregate in families. However, various measures of schizoid, schizotypal, and paranoid- significant methodological problems made the results like traits using self-report questionnaires have nearly uni- uncertain. Distel et al estimated that additive genetic fac- formly found significant heritability for these traits and tors explained 42% of the variance in borderline PD fea- failed to find shared environmental effects (eg, refs 29-33). tures assessed by self-report questionnaire, using data from Heritabilities are typically in the range of 35% to 60%. In three countries.40Non-shared environment accounted for a twin study using structured interview data, but based on the rest. In a subsequent extended twin-family study by the a clinical sample, Torgersen et al34found lower heritabil- same group the heritability of borderline PD features was ity estimates for paranoid PD (28%) and schizoid PD found to be 45%, but the genetic effects were both addi- (29%), but much higher heritability for schizotypal PD tive (21%) and dominant (24%).41Nonadditive effects are (61%). The method of ascertainment and the relatively difficult to detect using the classical twin model due to lack low number of participants make the estimates from this of statistical power.23 However, such effects have been study uncertain. In a more recent population-based study found for normal personality traits in twin-sibling studies of dimensional representations of the DSM-IV cluster A with large samples.42 PDs based on structured interviews, Kendler et al35esti- Results from a twin study based on structured interviews mated heritability to be 21% for paranoid, 28% for in a clinical sample suggest that heritability estimates for schizotypal, and 26% for schizoid PD. No shared envi- borderline, histrionic, and narcissistic PD were high, 69%, ronmental effects or sex differences were found. 63%, and 77% respectively.34 More recently, however, In twin studies unreliability of measurement will decrease Torgersen et al43conducted a population-based twin study 105 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 106 C l i n i c a l r e s e a r c h of dimensional representations of the DSM-IV cluster B Disorders in Appendix B PDs. Heritability was estimated to be 38% for antisocial PD, 31% for histrionic PD, 24% for narcissistic PD and In a population-based twin study of depressive PD, 35% for borderline PD. No shared environmental influ- Ørstavik et al46 found that liability could best be ences or sex or effects were found. explained by additive genetic and unique environmen- tal factors alone, with heritability estimates of 49% in Cluster C females and 25% in males. Unlike the results for the other DSM-IV PDs, both quantitative and qualitative A family study of the anxious-fearful cluster indicated sig- sex-differences were found corresponding to findings nificant familiality for DSM-III avoidant and dependent from studies on major depression.47Significant familial PD,44and in a clinically based twin study, heritability esti- aggregation has also been found for DSM-IV passive mates for avoidant, dependent, and obsessive-compulsive aggressive PD.48 PD were found to be 28%, 57%, and 77%, respectively.34 Results from a population-based study of dimensional Multivariate studies representations of DSM-IV Cluster C PDs,45 however, indicated that heritability estimates were similar for If heritability has been established, several more com- avoidant PD (35%), but lower for dependent (31%) and plex models can be employed to explore the nature and for obsessive-compulsive PD (27%), again illustrating the mode of action of the genetic risk factors.7Multivariate importance of method of ascertainment. This discrepancy analyses, which comprise models where several pheno- is probably in part due to difference in methods of ascer- types are included and different structures of the latent tainment. No shared environmental effects or sex differ- factors can be specified,20 can be used to estimate to ences have been found for cluster C PDs. what extent genetic and environmental risk factors are .28 .34 .31 .00 .24 .00 .33 .00 .37 .41 Figure 1. Genetic parameter estimates from best fitting model for ten DSM-IV personality disorders. Path estimates are standardized regression coef- ficients, so they must be squared to equal the proportion of variance accounted for in the dependent variable. A stands for additive genetic effects. The subscripts C and S stand, respectively, for common factor and disorder-specific effects. The first, second and third genetic com- mon factors are indicated by the subscripts , and . Paths with values ≥ +0.28 (which account for ≥ 8% of phenotypic variance) are col- C1 C2 C3 ored with the first, second, and third common factor indicated by, respectively, red, green, and blue and the disorder-specific factors by magenta. Paths not exceeding the + 0.28 cutoff are depicted in gray. From ref 52: Kendler KS, Aggen SH, Czajkowski N, et al. The structure of genetic and environmental risk factors for DSM-IV personality disorders a multivariate twin study. Arch Gen Psychiatry. 2008;65:1438-1446. Copyright © American Medical Association 2008 106 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 107 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 specific to a given PD or shared in common with other The results are also to a large extent consistent with a PDs or axis I disorders, and thus to investigate sources prior multivariate twin study of the dimensional classi- of comorbididity.49,50By including measures of the same fication system of personality disorder trait mentioned phenotypes on different points in time, they can also be above26in which Livesley et al identified four genetic used to determine if genetic effects differ over time in factors loading on four phenotypic dimensions called a developmental perspective. “emotional dysregulation,” “dissocial behavior,” “inhi- bition,” and “compulsivity.” DSM-IV personality disorders Taken together these results indicate that genetic risk factors for DSM-IV PDs do not reflect the cluster A, B, Cluster A PDs have been found to aggregate in families and C typology. However, this is well reflected in the of probands with schizophrenia (see below). Familial structure of the environmental risk factors, suggesting coaggregation has also been found for borderline PD and that the comorbidity of PDs within clusters is due to antisocial PD39and for borderline PD and all the other environmental experiences. cluster B PDs,51 as well as for the DSM-III cluster C PDs.44A population-based twin study including all PDs Personality disorders and Axis I disorders within cluster B indicated that borderline PD and anti- social PD appeared to share genetic risk factors above Several lines of evidence indicate specific axis I/axis II and beyond those shared in common with the other clus- relationships,54,55suggesting that common genetic or envi- ter B disorders,43and a twin study of cluster C PDs sug- ronmental liability factors might predispose to several gested that genetic factors influencing obsessive-com- disorders within clusters that transcend the axis I/axis II pulsive PD appeared to be relative specific to this division.13,49,56 disorder.45Kendler et al, in the only population-based multivariate twin study including all 10 DSM-IV PDs Schizophrenia that has been published,52 found that the best-fitting model included three genetic and three environmental A number of family and adoption studies have exam- factors in addition to disorder-specific factors. The struc- ined the risk for paranoid, schizoid, and schizotypal PDs ture of the genetic factors is shown in Figure 1. The first in relatives of schizophrenic and control probands. While genetic factor (A ) had high loadings on PDs from all 3 a few studies can be found where all threecluster A PDs C1 clusters including paranoid, histrionic, borderline, narcis- are at increased risk in relatives of schizophrenic sistic, dependent, and obsessive-compulsive PD. This fac- probands,57,58 more common are studies that find that tor probably reflects a broad vulnerability to PD pathol- only schizotypal PD59-63or schizotypal PD and paranoid ogy and/or negative emotionality, and is related to PD64have a significant familial relationship with schizo- genetic liability to the normal personality trait neuroti- phrenia. Taken together, these results suggest that cism. The second genetic factor (A )was quite specific schizotypal PD has the closest familial relationship to C2 with substantial loadings only on borderline and antiso- schizophrenia, followed by paranoid and schizoid PD, cial PD. This is consistent with the results from the above- and are consistent with the hypothesis that a common mentioned family studies,39and suggests genetic liability genetic risk factor for cluster A PDs reflects—in the gen- to a broad phenotype for impulsive/aggressive behavior. eral population—the liability to schizophrenia.35 The The third factor identified (A )had high loadings only extended phenotype believed to reflect this genetic lia- C3 on schizoid and avoidant PD. This can be interpreted in bility to schizophrenia is often described by the term several ways. It might in part reflect genetic risk for schiz- schizophrenia spectrum. Schizotypal PD has been sug- ophrenia spectrum pathology (see below). From the per- gested to be the prototypical disorder in this spectrum.65 spective of the five-factor model of normal personality it In a recent family study, Fogelson et al66 showed that reflects genetic liability for introversion.53 Finally, it is avoidant PD, currently classified in DSM cluster C, also noteworthy that obsessive-compulsive PD had the high- occurred more frequently in relatives of probands with est disorder-specific genetic loading, which parallels prior schizophrenia even after controlling for schizotypal and findings that this PD shares little genetic and environ- paranoid PD. This replicates findings from earlier stud- mental liability with the other cluster C PDs. ies,58,67 and suggest that avoidant PD should also be 107 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 108 C l i n i c a l r e s e a r c h included in this spectrum. It is also in part in accordance substance-use disorders (often called externalizing dis- with the results from the multivariate study by Kendler orders) share a common genetic liability (eg, refs 68,74). et al described above,52where avoidant and schizoid PD In a family-twin study, Hicks et al75found that a highly share genetic liability. heritable (80%) general vulnerability to all the exter- nalizing disorders accounted for most of the familial Internalizing disorders resemblance. Disorder-specific vulnerabilities were detected for conduct disorder, alcohol dependence, and Mood and anxiety disorders (often called internalizing drug dependence, but not for antisocial PD. The same disorders) share genetic and environmental liability fac- group also reported an association between externaliz- tors with each other,68and with the normal personality ing disorders and reduced amplitude of the P3 compo- trait neuroticism,69which correlates strongly with several nent of the brain event-related potential, suggesting that PDs, especially in cluster B and C.53 this could be a common biological marker for the bio- Family studies indicate that borderline PD and major logical vulnerability to these disorders.76 depression share familial risk factors.51,70In a population- based multivariate twin study of major depression and Longitudinal studies DSM-IV PDs, Reichborn-Kjennerud et al71 found that dimensional representations of borderline PD from clus- Most of the genetic studies that have investigated ter B, avoidant PD from cluster C, and paranoid PD from changes in genetic influences on PDs over time have cluster A were all independently and significantly associ- used measures related to antisocial PD. The following ated with increased risk for major depression. Multivariate examples illustrate the potential of longitudinal quan- twin modeling indicated that one latent factor accounted titative genetic methods. In a twin study, Lyons et al77 for the genetic covariance between major depression and demonstrated that the genetic influence on symptoms of the three PDs. The genetic correlations between major DSM-III-R antisocial PD was much more prominent in depression and borderline, avoidant, and paranoid PD adulthood than in adolescence. Silberg et al78studying were respectively +0.56, +0.22, and +0.40. No sex differ- twins between 10 and 17 years of age found a single ences or shared environmental effects were found. These genetic factor that influenced antisocial behavior begin- results indicate that vulnerability to general PD pathology ning at age 10 through young adulthood, a shared envi- and major depression are closely related. In a bivariate ronmental effect beginning in adolescence, a transient twin study, Ørstavik et al72found that a substantial part of genetic effect at puberty and genetic influences specific the covariation between major depressive disorder and to adult antisocial behavior. In another recent twin study depressive PD was accounted for by genetic factors with of externalizing disorders, biometric analyses revealed a genetic correlation of 0.56. Results from another popu- increasing genetic variation and heritability for men but lation-based twin study, investigating the sources of co- a trend toward decreasing genetic variation and increas- occurrence between social phobia and of avoidant PD in ing environmental effects for women.79 females, indicated that social phobia and avoidant PD were influenced by identical genetic factors, whereas the Gene-environment interplay environmental factors influencing the two disorders were uncorrelated.73This suggests that an individual with high In the traditional models of disease etiology in psychiatric genetic liability will develop avoidant PD versus social epidemiology the causal pathway is conceptualized as phobia entirely as a result of environmental risk factors moving from the environment to the organism. However, unique to each disorder, which is in accordance with the since genes influence behavior, genetic factors can indi- hypothesis of underlying psychobiological dimensions cut- rectly influence or control exposure to the environment,20 ting across the axis I/ axis II classification system. called gene-environment correlation.20,80,81Genetic factors can also control an individual’s sensitivity to the environ- Substance-use disorders ment, ie, genetic factors influence or alter an organism’s response to environmental stressors.20,80,81This is usually Numerous family, adoption and twin studies have called gene-environment interaction. In quantitative stud- demonstrated that antisocial PD, conduct disorder, and ies of gene-environment interplay, genetic factors are 108 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 109 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 either inferred (eg, disorder in biological parent in adop- Molecular genetic studies tion studies) or modeled as a latent variable.80,82 Twin and adoption studies have provided much of the Traditionally, linkage and association studies have been evidence for gene-environment correlations by demon- most commonly used for mapping disease loci.94Most of strating genetic influences for a number of measures of the molecular genetic studies of PDs has been done the environment.80Overall, the evidence from twin and using hypothesis-driven candidate gene association stud- adoption studies suggests that gene-environment corre- ies95focusing on particular genes related to the neuro- lations are mediated by heritable personality traits and transmitter pathways, especially in the serotonergic and possibly PDs.81,83,84 dopaminergic systems. Although the number of genetic The initial indications that gene-environment interac- association studies are increasing exponentially, only a tion was likely to be operating came from adoption and very small fraction of positive results are replicated.96,97 twin studies.85 Gene-environment interaction was Until further replications are published the results demonstrated in an adoption study as early as in 1974, reviewed below must therefore be considered tentative. when Crowe86found that early institutional care was a risk factor for later antisocial behavior only when a Cluster A genetic risk factor was present. In another adoption study, Cadoret et al87 found significant gene-environ- Consistent with the hypothesis that schizophrenia and ment interaction by showing that there was a negligible related PDs are linked to dopaminergic dysfunction, risk for antisocial behavior from a genetic risk alone Rosmond et al98found that Cluster A PDs were associ- (antisocial behavior in the biological parent), no effect ated with a polymorphism in the gene coding for the of an adverse adoptive family environment alone, but a dopamine 2 receptor (DRD2). Building on results from substantial effect when both were present. The finding quantitative genetic studies indicating that common was replicated in a later study with a larger number of genetic risk factors exist for schizotypal PD and schizo- adoptees,88Jaffe et al,89using a twin design, found sig- phrenia, Stefanis et al99examined the potential impact nificant gene-environment interaction with respect to of SNPs within the four most prominent candidate genes childhood maltreatment and the development of anti- for schizophrenia. Dysbindin (DTNBP1) and D-amino- social behavior, and in a twin study Tuvblad et al90 acid oxidase (DAAO) both showed associations with demonstrated a significant gene-environment interac- symptoms of schizotypy. Similarly, Fanous et al100using a tion by showing that the heritability for adolescent anti- linkage approach, found that a subset of schizophrenia social behavior is higher in socioeconomic advantaged susceptibility genes also affect schizotypy in nonpsy- environments. Using an advanced family design, chotic relatives. Significant associations with schizotypal Feinberg et al91recently found an interaction of geno- personality traits have also been found in several stud- type and both parental negativity and low warmth pre- ies with polymorphisms in the gene coding for catechol- dicting antisocial behavior. Significant gene-environ- O-methyltransferase (COMT)100,102,103an enzyme involved ment interaction has also been demonstrated in in the degradation of catecholamines, and linked to the schizophrenia spectrum disorders. In an adoption study etiology of schizophrenia.104 Tienari et al92showed that there was a significant asso- ciation between disordered rearing and the diagnosis of Cluster B schizophrenia spectrum disorder in the offspring of mothers with but not in offspring of mothers without Multiple lines of evidence suggest that dysfunction in the the diagnoses. In a community based twin study, Hicks serotonin (5-HT) system is associated with impulsivity, et al demonstrated a significant gene-environment aggression, affective lability, and suicide. Genes linked interaction with a number of environmental risk factors to the function of this neurotransmitter can therefore be showing that greater environmental adversity was asso- considered possible candidate genes for borderline and ciated with increased genetic risk for antisocial PD and antisocial PD. Kennedy and coworkers found that bor- substance use disorders.93Significant gene-environment derline PD was associated with polymorphisms in the interaction has also been demonstrated in quantitative serotonin transporter gene (5-HTTLPR),105and poly- studies of anxiety and mood disorders.81 morphisms in the gene coding for the catabolic enzyme 109 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 110 C l i n i c a l r e s e a r c h monoamine oxidase A (MAOA), involved in the regu- authors to conclude that DRD3 may contribute to the lation of biogenic amines like serotonin, norepinephrine, development of obsessive-compulsive PD.121 and dopamine,106 but not polymorphisms in the gene coding for the serotonin 5-HT2A receptor.107Recently Gene-environment interplay the group has conducted a gene-gene interaction study with a number of polymorphisms in seven serotonin Few studies of gene-environment correlation using mea- genes (including the three mentioned above), conclud- sured genes and measured environments have been pub- ing that “serotonin genes and their interaction may play lished. Dick et al121found that individuals who had a poly- a role in the susceptibility to borderline PD.”108Other morphism in a gene (GABRA2) associated with alcohol groups have reported similar findings. A main effect of dependence were less likely to be married, in part because the 5-HTTLPR polymorphism on borderline PD has they were at higher risk for antisocial PD and were less been found in bulimic women,109and Lyons-Ruth et al likely to be motivated by a desire to please others. Other found a significant relationship between the short results confirm the existence of gene-environment corre- 5HTTLPR allele and both borderline and antisocial lation with measured genes in both the dopaminergic and PD,110but other studies have failed to find an association serotonergic system, and provide preliminary support for between this polymorphism and cluster B PDs.111 the finding that correlations are mediated by behavioral Polymorphisms in the MAOA gene have been found to and personality characteristics.84 be associated with cluster B PDs,112 and antisocial Gene-environment interaction studies using identified traits.113 Tryptophan hydroxylase is the rate-limiting susceptibility genes rather than unmeasured latent enzyme in the serotonin metabolic pathway. Two genes genetic factors can provide more secure estimates.84 related to this enzyme, the tryptophan hydroxylase 1 and Based on results from quantitative genetic studies show- 2 genes (TPH1and TPH2), have been associated with ing gene-environment interaction for antisocial behav- borderline PD114and personality traits related to emo- ior, Caspi et al123studied the association between child- tional instability, as well as to cluster B and cluster C hood maltreatment, and a functional polymorphism in PDs.115Taken together, these findings suggest that bor- the promoter region of the MAOA gene on antisocial derline and antisocial PD and possibly also the other behavior assessed through a range of categorical and cluster B PDs, are influenced by genes regulating the dimensional measures using questionnaire and interview serotonergic system. They are also consistent with the data plus official records. The results showed no main finding of shared genetic influence on borderline PD effect of the gene, a main effect for maltreatment and a and antisocial PD, and on borderline PD and the other substantial and significant interaction between the gene cluster B PDs found in multivariate twin studies.43,52 and adversity. The maltreated children whose genotype conferred low levels of MAOA expression more often Cluster C developed conduct disorder and antisocial personality than children with a high activity MAOA genotype. It has previously been suggested that the 5-HTTLPR Foley et al124replicated this finding and extended the ini- polymorphism was associated with anxiety-related tial analysis by showing that the gene-environment inter- traits,116but later studies have yielded conflicting results action could not be accounted for by gene-environment (see ref 117). Patients diagnosed with cluster C PDs, correlation. Other studies have failed to replicate the have not been found to be significantly higher in the fre- gene-environment interaction effect (eg, ref 125). In a quency of the short form allele of the 5- recent meta-analysis, however, the original finding was HTTLPR.111Recent results, on the other hand, indicate replicated. In addition the findings was extended to that variations in the COMT gene contribute to genetic include childhood (closer in time to the maltreatment), risk shared across a range of anxiety-related pheno- and the possibility of a spurious finding was ruled out by types.118,119Joyce120found an association between avoidant accounting for gene-environment correlation.126 The and obsessive-compulsive PD symptoms and the interaction between MAOA and childhood maltreat- dopamine D3 receptor (DRD3) polymorphism. In a ment in the etiology of antisocial PD appear to be one later study and a meta-analysis, the finding for obsessive- of the few replicated findings in the molecular genetics compulsive symptoms were replicated, leading the of PDs. 110 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 111 Genetic epidemiology of personality disorders - Reichborn-Kjennerud Dialogues in Clinical Neuroscience - Vol 12 .No. 1 .2010 Future directions Methods like genome-wide association studies,128 analyses of copy-number variation,129studies of rare Information from genetic epidemiologic studies can con- genetic variants,130 epigenetic methods,131 and deep tribute to improvement in the validity of diagnoses of men- sequencing of genomic regions132 have not yet been tal disorders, and thereby a more empirically based classifi- applied to PDs, and will hopefully contribute to our cation system.49,56,127 Several lines of evidence, including understanding of the genetic etiology of these disor- multivariate twin studies, have shown that common axis I ders in the future. One problem is, however, that the disorders can be divided into two main groups (internalizing current phenotypes might be inadequate.128It is highly and externalizing) based on shared etiological factors.49,68 unlikely that the new DSM-V classification of PDs will Currently an alternative classification system are being con- provide a solution. A strategy that has been proposed sidered for DSM-V based on the hypothesis that, in addition to increase the rate of success for molecular genetics to phenotypic similarity, spectra or clusters of disorder can in psychiatry is the use of endophenotypes, defined as be identified based on shared liability or risk factors.56Such a heritable characteristic that is along the pathway clusters transcend the axis I-axis II division. Multivariate twin between a disorder and genotype.5Although the strat- studies, including a comprehensive number of axis I and axis egy has not yet proven to be successful,133it has been II disorders, could provide new important insights relevant suggested that this approach should be applied to the to this proposal and further clarify the etiology of mental dis- study of PDs by using clinical dimensions like for orders by identifying genetic and environmental risk factors example affective instability, impulsivity, and aggres- shared in common between groups of disorders. sion instead of diagnoses.134 ❏ REFERENCES 15. Sheets E, Craighead WE. Toward an empirically based classification of personality pathology. Clinl Psychol Sci Pract. 2007;14:77-93. 1. American Psychiatric Association. Diagnostic and Statistical Manual of 16. Oldham JM, Skodol AE. Charting the future of axis II. J Personal Disord. Mental Disorders. 3rd ed. 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Personality disorder and Axis I psychopathology: the prob- 29. Kendler KS, Heath A, Martin NG. A genetic epidemiologic study of self- lematic boundary of Axis I and axis II. J Personality Disord. 2003;17:90-108. report suspiciousness. Comp Psychiatry. 1987;28:187-196. 111 DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 112 C l i n i c a l r e s e a r c h La epidemiología genética de los trastornos Epidémiologie génétique des troubles de la de personalidad personnalité Los estudios de epidemiología genética señalan que Des études d’épidémiologie génétique montrent los diez trastornos de personalidad (TP) clasificados que les 10 troubles de la personnalité (TP) classés en el eje II del DSM-IV tienen una herencia leve a sur l’axe II du DSM-IV sont légèrement à modéré- moderada. Los factores ambientales compartidos y ment transmissibles. Les facteurs génétiques non genéticos no aditivos son de importancia menor o additifs et les facteurs environnementaux partagés carecen de ésta. No se han identificado diferencias sont de peu ou sans importance et il n’y a pas de por sexo. Los estudios multivariados sugieren que différences selon le sexe. Des études multivariées la amplia comorbilidad entre los TP se puede expli- suggèrent que trois facteurs de risque génétiques car por tres factores de riesgo ambientales y gené- et environnementaux courants peuvent expliquer ticos comunes. Los factores genéticos no reflejan la la comorbidité importante entre les TP. Les facteurs estructura de grupos del DSM-IV, pero sí: 1) la alta génétiques ne reflètent pas la structure en cluster vulnerabilidad para la patología de los TP o para la du DSM-IV mais plutôt : 1) une grande vulnérabilité emocionalidad negativa, 2) la alta impulsividad/baja aux TP ou à une émotivité négative ; 2) une impul- afabilidad y 3) la introversión. Los factores de riesgo sivité importante/peu d’amabilité ; 3) une introver- genéticos y ambientales comunes contribuyen a la sion. Des facteurs de susceptibilité génétiques et comorbilidad entre parejas o grupos de trastornos environnementaux communs participent à la de los ejes I y II. Los estudios de genética molecular comorbidité entre les paires ou les groupes des de los TP, principalmente los estudios de asociación troubles de l’axe I et de l’axe II. Des études de géné- de genes candidatos, señalan que están involucra- tique moléculaire des TP, pour la plupart des études dos los genes vinculados a los sistemas de neuro- d’association de gène candidat, montrent que sont transmisión, principalmente serotoninérgicos y impliqués les gènes liés aux voies des neurotrans- dopaminérgicos. Estudios a futuro, que utilicen metteurs, surtout dans les systèmes sérotoniner- métodos más nuevos como la asociación del giques et dopaminergiques. Des études futures, uti- genoma completo, pueden aprovechar el empleo lisant la méthodologie de recherche d'associations de endofenotipos. sur génome entiers pourraient bénéficier de l'utili- sation d' endophénotypes. 30. Claridge G, Hewitt JK. A Biometrical study of schizotypy in a normal 38. Rhee SH, Waldman ID. Genetic and environmental influences on anti- population. Person Individ Diff.1987;8:303-312. social behavior: a meta-analysis of twin and adoption studies. Psychol Bull. 31. Kendler KS, Hewitt JK. The structure of self-report schizotypy in twins. 2002;128:490-529. J Personal Disord. 1992;61-17. 39. White CN, Gunderson JG, Zanarini MC, Hudson JI. Family studies of bor- 32. Linney YM, Murray RM, Peters ER, Macdonald AM, Rijsdijk F, Sham PC. derline personality disorder: A review. Harv Rev Psychiatry. 2003;11:8-19. A quantitative genetic analysis of schizotypal personality traits. Psychol Med. 40. Distel MA, Trull TJ, Derom CA, et al. 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Behav Genet. 2005;35:707-721. of DSM-IV Cluster A personality disorders in a population-based sample of 43. Torgersen S, Czajkowski N, Jacobson K, et al. Dimensional representa- Norwegian twins: a multivariate study. Psychol Med. 2006;36:1583-1591. tions of DSM-IV cluster B personality disorders in a population-based sample 36. McGlashan TH, Grilo CM, Sanislow CA, et al. Two-year prevalence and of Norwegian twins: a multivariate study. Psychol Med. 2008;38:1617-1625. stability of individual DSM-IV criteria for schizotypal, borderline, avoidant, 44. Reich JH. Familiality of DSM-III dramatic and anxious personality clus- and obsessive-compulsive personality disorders: toward a hybrid model of ters. J Nerv Ment Dis. 1989;177:96-100. axis II disorders. Am J Psychiatry. 2005;162:883-889. 45. Reichborn-Kjennerud T, Czajkowski N, Neale MC, et al. Genetic and 37. Kendler KS, Myers J, Torgersen S, Neale MC, Reichborn-Kjennerud T. environmental influences on dimensional representations of DSM-IV clus- The heritability of cluster A personality disorders assessed by both personal ter C personality disorders: a population-based multivariate twin study. interview and questionnaire. Psychol Med. 2007;37:655-665. Psychol Med. 2007;37:645-653. 112

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