Psychiatric Genetics and Forensic : A Review

Stephen H. Dinwiddie, MD

Research in psychiatric genetics has been revolutionized by the development of new and powerful molecular genetic techniques. Family, twin, and adoption studies of antisocial personality disorder (ASPD) and criminality are reviewed, and ramifi- cations of new research methods for the study of antisocial behavior are considered. Implications of these developments for are discussed.

Recent advances in molecular genetic Over time the list of familial psychiatric techniques and psychiatric genetics hold illnesses has grown to include alcohol- the promise that heritable factors asso- ism,' other substance abuse,2 schizo- ciated with increased liability for psychi- ~hrenia,~unipolar depression and atric illness as well as those influencing manic-depressive illness,4, Briquet's normal personality variation may be ~yndrorne,~.obsessive-compulsive dis- identified, ultimately leading to charac- order,' and anxiety states,lO," among terization of their structure and function others. at the molecular level. Such analysis The inheritance of criminal behavior may ultimately allow researchers the op- has likewise been studied for dec- portunity more fully to understand how ades.l2?l3 Such studies generally take one inborn, heritable traits and postnatal en- of two approaches: Either studying the vironment interact in the development transmissibility of criminality between of psychopathology. The purpose of this generations, or investigating the famil- article is therefore to review recent de- iality of ASPD. It should be kept in velopments in psychiatric genetics, with mind, however, that while there is con- particular emphasis on studies of crimi- nality and Antisocial Personality Disor- siderable overlap, ASPD is not equiva- der (ASPD). lent to criminality, and both may differ in important respects from antisocial be- Family Studies havior, which does not necessarily imply The familial nature of many psychi- either early onset or arre~t.'~-'~More- atric illnesses has long been recognized. over, from the standpoint of genetic studies, even ASPD, a reliable and vali- Dr. Dinwiddie is assistant professor of psychiatry, Washington University School of Medicine. Address dated diagnostic category, appears to be correspondence to Dr. Stephen H. Dinwiddie, Depart- a heterogeneous grouping.'', Is ment of Psychiatry, 4940 Children's Place, St. Louis, MO 63 1 10. Early family studies of criminality and Dinwiddie antisocial behavior, although consistent fewer women in the general population with the hypothesis that liability to such were diagnosed with ASPD, combined behavior had a heritable component, with the fact that women with ASPD generally share a number of methodo- tended to have a higher proportion of logic weaknesses such as biased ascer- affected relatives, also indicated that the tainment of cases, confounding of crim- sexes differed in threshold for expression inality with the effects of , of the trait, i.e., that affected women imprecise or inadequate classification of tended to be more deviant (from the criminality, and inadequate assessment population mean) in liability for the dis- of environmental factors.l2>l4 More re- order. cent studies, however, are also consistent A subsequent family study using felon with the presence of a familial compo- probands2' reported similar findings, re- nent of antisocial behavior and ASPD. vealing a phenotypic correlation be- In one of the first studies to diagnose tween relatives for ASPD of 0.425. They psychiatric disorders systematically further found that the familial factors among first-degree relatives of convicted (environmental and genetic) relevant to felons, Guze and coworkers19, 20 found the development of ASPD appeared to elevated rates of hysteria (Briquet's syn- be the same for men and women, with drome), sociopathy, alcoholism, and little evidence for sex-specific causes. drug addiction, but not other psychiatric It should be kept in mind that the disorders. Subsequently, Cloninger, finding of familiality does not mean that Reich, and Guze2' evaluated 86 felon all cases (or even the majority of cases) probands and 387 of their biological of an illness must be familial; it merely first-degree relatives. Blind to the pro- means that the illness is more prevalent band's diagnosis and using explicit di- among relatives of a proband with the agnostic criteria, they found the rate of illness than among the general popula- ASPD to be 17 percent among male tion. Family studies, moreover, are not relatives of male felons and four percent without limitations or pitfalls. Bias in among female relatives of male felons. ascertainment of probands for family Among relatives of female felons, the studies can lead to substantial over- or rate was higher for both men (36%) and underestimation of prevalence of famil- women (19%). For both male and fe- ial illness; similarly, excessively restric- male relatives, the rates were substan- tive or lenient definitions of illness or tially higher than in the general popula- "caseness" can lead to spurious or un- tion, indicative that the disorder was generalizable results. Unsystematic as- familial. They concluded that the data sessment of subjects or evaluation of best fit a model of multifactorial trans- family members by investigators not mission; that is, either multiple genes of blind to the proband's diagnosis can fur- relatively small individual effect, or a ther distort conclusions. Probability of combination of genetic and environ- consenting to interview or being avail- mental etiologic factors. The finding that able to be interviewed may be affected

328 Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 Psychiatric Genetics and Forensic Psychiatry by disease status; for example, if the Adoption studies in general may be disorder is associated with premature biased by factors such as selective or death, incarceration, and so forth. As- delayed placement of adoptees, and sortative mating can inflate the esti- some biological effects on the infant mated heritability of a disorder, whereas (such as prenatal exposure to alcohol or reliance on family history (as opposed other drugs) may persist indefinitely to direct interview) data is known to after placement in an adoptive home. underestimate prevalence of affected Interpretation of results of older adop- subjects.23 Estimates of familial rates tion studies of antisocial behavior is dif- may be confounded by secular trends in ficult, also, because of the same prob- disease prevalence or its transmissibil- lems noted for family studies, e.g., dif- Familiality of illness could be due ferences in assessing ASPD, other wholly or in part to a familial aggrega- psychopathology, and criminality, or tion of risk factors for the illness, rather failure to account for the possible effects than to the specific inheritance of the of substance abuse. Nonetheless, sub- illness or liability to it.25,26 stantial evidence for heritable factors in Finally, familiality does not necessar- adoptees has been found in Danish ily imply a genetic basis for inheritance. adoptees by Sch~lsinger~~and in US As Goodwin2' has pointed out, the abil- samples by Cr~we~~-~'and Cad~ret.~~ ity to speak French runs in families, but In contrast, B~hman,~~studying crim- one need not invoke a genetic cause of inal records and registrations for alco- French speaking. Other techniques, holism of 2324 adoptees in Sweden, therefore, are necessary in order to sep- found evidence for inheritance of alco- arate cultural from biological inherit- holism, but not criminal behavior. In ance. that study, a subsample matched for a number of parental characteristics; and Adoption Studies in Criminality contrasting the biological parents with and ASPD and without criminal records was used, In theory, adoption studies isolate with no differences seen in rates of crim- constitutional from acquired traits be- inality among either adopted men or cause the infant is raised by parents to women. whom he or she is not genetically re- Subsequently, however, Bohman, lated. A correlation between presence of Cloninger, and Sigvard~son~~reanalyzed a psychiatric illness in the biological, but data on 862 Swedish male adoptees of not adoptive, parents and in the child known paternity placed before the age would be evidence in favor of a biolog- of three years. In this sample, they iden- ically inherited, presumably genetic lia- tified a form of criminality (commission bility factor, whereas excess concord- of property offenses) that appeared to be ance with the adoptive parents would inherited separately from alcohol abuse. favor familial, but not genetic, transmis- Although this trait conveyed no protec- sion. tion against alcohol abuse, it appeared

Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 329 Dinwiddie distinct from alcohol-related criminal- disorders" (treatment for substance ity, characterized by repetitive commis- abuse or personality disorder) in the bi- sion of antisocial acts that were more ological parents were associated with often violent in nature. conviction for property crimes in the Further analyses35,36 indicated sub- child. Baker4' was able to estimate the stantial gene-environment interaction in relative contributions of genetic and en- the production of this behavior; 40 per- vironmental factors to these observed cent of those from high-risk prenatal phenotypic correlations, finding that in backgrounds reared in high-risk homes addition to high correlations for genetic became petty criminals, as compared to factors, the relationship appeared to be 2.9 percent of those from neither high- strongly mediated by correlated environ- risk biological nor environmental back- mental factors. Finally, Baker et aL4' grounds. Exposure to an exacerbating found that, although genetic and envi- environment in the absence of a high- ronmental influences apparently con- risk biological background was associ- tribute equally to liability for being a ated with a 6.7 percent rate of petty property criminal, women convicted of criminality, whereas presence of high- property crime tend to have a greater risk biological background without degree of genetic predisposition, a find- placement in a high-risk environment ing consistent with that of Cloninger et was associated with a rate of 12.1 per- aL2' cent. Cadoret, O'Gorman, Troughton, and Consistent with these findings, in a Hey~ood~~directly interviewed 127 study examining court convictions of male and 87 female adoptees and their 14,427 Danish adoptees as well as their adoptive parents; information on psy- biological and adoptive parents, Med- chiatric disorders among biological rel- nick, Gabrielli, and Hutchings3' found a atives was obtained from agency records. strong association in convictions for In their analysis, antisocial behavior in property offenses, but not violent first-degree biological relatives increased crimes, between biological parents and the odds of diagnosis of ASPD in male adoptive sons. Higher numbers of con- adoptees by a factor of 3.7. Among fe- victions were associated with higher male adoptees, the odds were increased rates of offending in the sons; moreover, by a factor of 1.9, but the relationship the proportion of repeated offenders was not statistically significant. A biolog- among adoptees increased with the ical background of alcoholism, by con- amount of crime seen in the biological trast, did not increase the risk of ASPD parents.38 Criminality in the adoptive among adoptees, although it did increase parents, by contrast, was not associated the odds for alcoholism among both with criminality in the sons. men and women. Finally, none of the Subsequent analyses of this large data environmental factors studied was asso- set have expanded these findings consid- ciated with increased odds for ASPD. A erably. M~fitt~~found that "antisocial replication study by the same investiga-

330 Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 Psychiatric Genefiics and Forensic Psychiatry tors using a different sample of ad~ptees~~because of variations in ascertainment, yielded very similar results, though in zygosity determination, and classifica- the latter study, problems in the adop- tion of criminality. A later twin study tive family such as antisocial behavior, by Chri~tiansen~~found substantially substance abuse, or other psychiatric dif- higher concordance for criminality (5 1 % ficulty were also found to be related to of 338 MZ pairs versus 26.2% of 637 the development of ASPD. Subsequent DZ male pairs); phenotypic correlation analyses44also found evidence for gene- was estimated at .600 for MZ twins and environment interaction, with lower so- .407 for DZ pairs. cioeconomic status associated with in- By contrast, Dalgard and K~inglen,~~ creased risk for ASPD in those with an studying 138 Norwegian twin pairs, antisocial biological background. found concordance rates of 25.8 percent and 14.9 percent in MZ and DZ twins, Twin Studies respectively. However, after controlling Thus, adoption studies on balance for similarities in environment, they support the hypothesis that some of the found that MZ-DZ differences in con- factors contributing to liability for cordance were so reduced that they con- ASPD or criminality are heritable. An- cluded that "hereditary factors are of no other line of evidence supporting the significant importance in the etiology of existence of heritable factors comes from common crime." twin studies. In the most commonly em- Later studies, however, cast doubt on ployed design, the difference in concord- that conclusion. Rowe;' ascertaining ance rates for illness in monozygotic 168 MZ and 97 same-sex DZ twin pairs (MZ) versus same-sex dizygotic (DZ) through high schools, used an anony- twins is studied, the assumption being mous survey form to determine zygosity that environmental factors should be and antisocial behavior. By fitting var- comparable between twins, whereas ge- ious biometric models to the data, Rowe netic factors would differ, since MZ concluded that a purely environmental twins share the same genome, and DZ model (ignoring genetic effects) could twins share on average 50 percent of not sufficiently account for twin similar- their genes. Thus, excess concordance ities, whereas models accounting for ge- for a disorder among MZ twins would netic effects and specific environmental be evidence for genetic influence on the (i.e., factors not shared by both twins) development of illness. As with adoption factors, with or without a factor account- studies, twin studies have provided sup- ing for environmental influences com- port for the hypothesis of genetic liability mon to both twins (common environ- factors in and affective ment), satisfactorily explained twin sim- illness3 as well as substance abuse.45 ilarities. Early twin studies of criminality ap- Rowe and Osg~od~~extended the peared to support the role of genetic analysis on this sample to correlations factors,12 but are difficult to interpret between self-reported antisocial behavm

Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 33 1 Dinwiddie ior and association with delinquent tors in antisocial behavior comes from peers, commonly felt to be a contribut- study of physiologic parameters in anti- ing factor to antisocial behavior in ado- social individuals. It has long been lescents. Partitioning the relationship known that group differences between into genetic, common environmental, criminals and controls exist on a num- and specific environmental compo- ber of measures, such as electrodermal nents, they found that most of the phe- responses, resting heart rate, and orient- notypic resemblance between the two ing responses to various stimuli, as well traits could be explained by genetic fac- as showing EEG evidence of cortical un- tors, (6 1 %) with common environmen- derar~usal.~'.52 These factors may in tal factors and environmental factors turn be related to a repeated finding that specific to one co-twin less important, criminals demonstrate impairment on a accounting for 23 percent and 16 per- variety of neuropsychological tasks,53 cent of the observed correlations be- tween male twins, respectively. For fe- particularly those that require passive male twin pairs, estimates were very sim- avoidance or inhibition of punished be- ilar (64%, 17%, and 19%). ha~ior.~~,55 However, Carey49 has suggested that Numerous biochemical differences most twin studies of criminality do not between criminals and noncriminals adequately account for reciprocal inter- have also been ~uggested.~~A number of actions between twins, i.e., the possibil- studies have suggested a correlation be- ity that co-twins may influence each oth- tween low serotonin (as measured by er's likelihood of engaging in antisocial cerebrospinal fluid assay) and violence behavior. Using the Danish twin sample, or imp~lsivity,~'-~~although since low it was shown that such effects could not central levels of serotonin have also been be ignored without causing the impor- found in suicide victim^,^^-^' the rela- tance of genetic factors to be substan- tionship appears nonspecific. tially overestimated. Many of these psychophysiological As with family and adoption studies, differences appear to be at least partially twin studies also have methodologic pit- under genetic ~ontrol.~',549 56, 62 Th US,a falls. Twins are a select population, tend- more complete understanding of the ge- ing to have higher rates of obstetric com- netic basis of antisocial behavior may plications, infant mortality, and older require studies of the inheritance of spe- mothers, whereas the assumption that MZ and DZ twins are treated similarly cific aspects of the ASPD phenotype, or that environmental influences (even rather than ASPD per se, analogous to intrauterine environment) are identical studies currently underway of the phe- may be q~estioned.~' notypes of alcoholism, schizophrenia, and bipolar illness.63 Physiologic Markers of Criminality and ASPD Heritability of Personality Traits Another line of evidence suggesting Thus, evidence from family, twin, and the role of biological susceptibility fac- adoption studies, combined with find-

332 Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 Psychiatric Genetics and Forensic Psychiatry ings of population differences on a va- descriptions of the specific genetic fac- riety of physiologic markers gives strong tors which may be involved in antisocial support to the overall conclusion that, behavior. But in order to assess their like most psychiatric illnesses, ASPD implications, it is necessary first to re- and criminality have a biologically her- view recent thinking about the heritabil- itable component; and from these stud- ity of personality traits in general, and ies several conclusions may be drawn. then to review the fundamentals of cur- First, heritable factors associated with rent molecular genetics. criminal behavior and ASPD can be dif- Unlike psychiatric illness, which is ferentiated from those predisposing to typically seen as a threshold phenome- substance abuse. Although the two syn- non (i.e., expression of the disorder is dromes are frequently confounded, they seen as exceeding the threshold of an appear to have different genetic compo- unmeasured underlying, normally dis- nents (at least for property crimes), tributed continuum of liability, so that though coexistent substance abuse ap- clinical description is dichotomous, pears to substantially exacerbate the either affected or unaffected), personal- course of criminal behavior. ity traits are generally conceptualized as Secondly, genetic factors are insuffi- continuous variables, approximately cient by themselves to fully explain an- normally distributed in the population. tisocial behavior. Thus, attention is Although a tremendous number of per- more properly focused not on establish- sonality assessment scales have been ing the cause of illness as nature versus proposed, most appear to measure nurture, but on characterizingand quan- roughly the same underlying factors, and tifling the role of genotype-environment most differences in personality can be interaction in the genesis of psychiatric explained fairly well in terms of varia- illness. tion along three independent axes.64 Finally, there is little evidence that It is unlikely that single loci that com- single genes of major effect play a signif- monly play a major role in determina- icant role in the inheritance and devel- tion of personality will be found.65,66 opment of antisocial behavior in most Rather, it appears that a number of cases. Rather, the genetic influence ap- genes, each of relatively small individual pears best explained by polygenic effects, importance, influence personality traits, i.e., a number of genes, each of relatively with the overall heritability of these traits modest power acting together. estimated to be between 30 percent and These conclusions are little different 50 percent. Even relatively modest ge- from what was known of the inheritance netic contributors may be relevant to the of antisocial behavior two or three dec- study of the inheritance of antisocial ades ago. However, several recent con- behavior. For example, measuring the ceptual and technical advances now en- effect of specific environmental factors able researchers to go from these classi- in the setting of a twin study design has cal techniques to more fundamental enormously increased statistical power

Bull Am Acad Psychiatry Law, Vol. 22, No. 3,1994 333 Dinwiddie when applied to other disorders, e.g., At the present time, depre~sion,~'and could appropriately be studies69may hold the most promise for used in studies of antisocial behavior, elucidating the genetics of psychiatric as well. Another potentially valuable illness. The rationale for linkage studies method is quantitative trait loci (QTL) rests on the fact that the normal human analysis, a technique whereby it may be has 23 pairs of chromosomes, 22 auto- possible to establish linkage to loci that somes, and two sex chromosomes. These individually account for small amounts can be thought of as strings of genes, of the variance of a given trait.68 and while the actual DNA sequence may differ between individuals (or even be- Genetic Linkage Studies in tween homologous chromosomes in the Psychiatric Illness same individual) at a given point or Up to this point, much has been made locus, the ordering of the loci is the same of the inheritance of personality traits or for everyone, barring chromosomal liability characteristics, but mode of in- translocations. Since the normal situa- heritance has been neglected. By mod- tion is that everyone has two copies of eling parameters such as population fre- each chromosome (one inherited from quency of alleles, their degrees of pene- each parent), particular DNA sequences trance and dominance, and applying at a given locus in principle can be traced these models to known pedigrees (seg- from parent to child. (Obviously, in regation analysis), multiple hypotheses practice the sequences must differ at that about mode of inheritance (single major locus in the parents in order to be fully locus or polygenic effect, primarily ge- informative.) netic or multifactorial influences, etc.) The various DNA sequences that can may be tested, thus significantly narrow- occur at that locus are referred to as ing the field of possible ways susceptibil- alleles; there may be few or many such ity to illness might be inherited. If variants to be found at a given locus. models are constrained to remain within The genotype of the individual at that bounds suggested by available data re- locus is determined by the allele actually garding these parameters, the technique found at that site on each of the two may be of significant value in supporting chromosomes. The phenotype of the in- some possible modes of inheritance and dividual is the observable expression of eliminating others-although, of course, the genotype that often therefore must as with any model-fitting exercise, con- be inferred rather than directly observed. struction of a model that cannot be re- Perhaps the best understood example is jected is not identical to confirming a the classical Mendelian situation where given mode of inheritance. Information two alleles (one dominant, one recessive) about likely inheritance patterns may be exist for a given locus. In this case, the of great use, however, especially if ge- observable characteristic (or phenotype) netic linkage studies are to be under- will vary depending on the genotype at taken. that locus: two recessive alleles (homo-

334 Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 Psychiatric Genetics and Forensic Psychiatry zygous recessive), two dominant alleles that the characters will be transmitted (homozygous dominant), or one of together approximates the probability of each (heterozygous). Assuming com- cotransmission of characters on different plete dominance, the latter two condi- chromosomes, i.e., 0.5. Similarly, cross- tions will express the same phenotype. ings over between two loci become less This scenario is frequently an over- and less likely as the distance separating simplification, however. Most such the loci decreases. Thus, the null hypoth- characteristics are not clearly dominant esis of no linkage means that 8 = 0.5; a or recessive, so that the heterozygous value of 8 significantly lower is evidence condition may show intermediate char- for linkage. Generally, rather than di- acteristics; moreover, at many loci, a rectly comparing odds of observed val- large number of alleles exist, resulting in ues to odds under the null hypothesis, a wide range of possible phenotypic researchers use the logarithm of these expression. Furthermore, as far as is cur- odds, or lod score, generally accepting a rently known in psychiatric genetics, lod score of 3 or greater as evidence in phenotypic characteristics of interest favor of linkage, and a score of less than rarely (if ever) depend only on gene -2 as evidence against expression at one locus. Until relatively recently, linkage stud- When two characters are consistently ies were severely hampered by a lack of cotransmitted within a pedigree, they are useable genetic markers. With the wide- considered linked. Given the above dis- spread use of endonucleases (enzymes cussion, it would seem that any two that cleave DNA at specific points), characters found on the same chromo- however, numerous heritable differ- some would always be inherited to- ences have been found in sequences gether; the fact that this is not so is due of DNA that could be cleaved. These to the phenomenon of crossing over. restriction-fragment-length polymorphisms During meiosis, the paired chromo- (RFLPs) are easily separated based on somes become closely approximated, electrophoretic mobility and have been and indeed overlap. Breaks in the chro- used with great success as genetic markers. mosomal material occur at these junc- Unfortunately, not all such markers are tures and as the breaks are repaired ho- informative (90% of polymorphic mark- mologous portions of DNA are ex- ers have a heterozygosity of less than changed. It is this altered chromosome 50%); however, techniques focusing on that is passed on in the gamete. highly informative regions such as sites Thus, the greater the distance between with variable numbers of tandem repeats, two loci on the same chromosome, the or VNTRs (stretches of DNA with re- greater the "recombination fraction" (8), peated C-A base sequences) have substan- i.e., the chance that the two characters tially improved informativene~s.~~,~~ will be independently transmitted. As Other new approaches, such as applica- the distance between loci on the same tion of polymerase chain reaction (PCR) chromosome increases, the probability technology to expand the amount of

Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 335 Dinwiddie genetic information available to re- well as exposure to putative environ- searchers, or large-scale cloning of seg- mental risk factors. ments of the human genome via yeast Other technical difficulties in psychi- artificial chromosomes (YACs) may atric genetic linkage studies include er- also improve researchers' abilities to rors or diagnostic instability in assess- identify specific genetic factors in a va- ment (since there are no diagnostic lab- riety of psychiatric disorders.75By use of oratory tests), variable penetrance of the these and other markers, the technology character of interest, variable age-of- has, in fact, advanced to the point of onset of illness, and phenotypic vari- making a high-resolution map of the ance. Moreover, major psychiatric ill- human genome an attainable goal.76 nesses are thought to be etiologically Once a putative disease locus has been heterogeneous; that is, similar illness demonstrated to be linked to a genetic presentations may be caused in a variety marker, it can be precisely located, e.g., of ways, including more than one ge- through "walking the chromosome" netic mechani~rn.~~ starting from the marker locus by use of It is therefore understandable that, cloned, overlapping DNA fragments, while researchers have reported evidence until the DNA sequence of interest is for linkage in several psychiatric disor- characterized. This should lead to iden- ders, confirmation so far has proven elu- tification of the gene product or function sive. Currently, a number of techniques and thus to better understanding of dis- are being developed to address these dif- ease pathophysiology at the molecular ficulties. It may prove more practical, 78 for example, to evaluate linkage with a This technology has proven most use- specific phenotypic character of the ill- ful for diseases inherited in a classical ness, rather than the entire syndrome. Mendelian fashion, e.g., Huntington's Use of large, extended pedigrees with disease or Duchenne muscular dystro- multiple affected relatives for linkage However, for common, complex studies should minimize the problem of disorders which are strongly genetically etiologic heterogeneity (since affected influenced, such as certain cancers, ath- family members are more likely to have erosclerotic cardiovascular disease, and the same form of illness); statistical many psychiatric disorders, the precise methods are being developed to assign mode of genetic inheritance is not probabilities of "caseness" rather than known. This means that researchers classify in an all-or-none fashion, meth- must make a variety of assumptions re- ods of multilocus linkage analysis have garding transmission, chief among them been proposed, as have ways of account- that a single locus of major effect that ing for environmental influences on risk can be linked to a marker exists, though for development of psychiatric ill- it may be modified by presence of other nes8'. 82 While these techniques have genes or a variety of environmental fac- not yet been applied to criminality or tors, such as secular trends in illness as ASPD, such linkage efforts are currently

336 Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 Psychiatric Genetics and Forensic Psychiatry underway in studies of schizophrenia, low and high-risk groups. Indeed, for manic-depressive illness, alcoholism, some forms of criminality this process and Alzheimer's disease. has begun, as researchers have at- Gene-environment Interaction tempted to identify more homogeneous form^.^^-^'? 39, 83 Furthermore, as is begin- Given the evidence supporting the ning to occur for other psychiatric dis- role of environmental factors in the gen- orders such as depression, by controlling esis of criminality and ASPD, it is likely for genetic factors (e.g., in twin study that further advances will come not just designs), use of behavioral genetic from refinements in molecular genetic techniques should allow researchers to techniques, but from the study of gene- identify environmental risk factors and environment interactions: The disparate characterize their influences on different effects specific genes have under differ- genotypes with a high degree of preci- ent conditions. It is well understood that ion.^^-^^ gene effects may manifest differently with changes in the environment; for Forensic Implications example, someone heterozygous for sic- Promising as these research develop- kle cell anemia will be asymptomatic at ments are, the moderate degree of her- sea level, but may develop sickling at itability of antisocial behavior suggests high altitudes. Similarly, children with that if genetic markers can be identified, phenylketonuria, if exposed to normal they will likely prove to be of limited levels of dietary phenylalanine, develop discriminatory power. Because antiso- mental retardation that may be mini- cial behavior appears to be associated mized or prevented by environmental with a number of factors (including en- manipulation, i.e., restricting phenylal- vironmental and experiential influ- anine intake. ences), one may predict that many cases Although it is a long jump from such would be genetic "false-negatives" (i.e., simple Mendelian disorders to the com- would be individuals without the puta- plex, polygenic factors that interact with tive genetic risk factors or risk indicators environmental influences to determine who nonetheless commit antisocial personality or psychiatric illness, the acts). Conversely, it is doubtful that ge- logic remains the same. By classifying netic factors would by themselves be individuals based on both biological and either necessary or sufficient causes of environmental risk factors, behavioral most antisocial behavior; thus, a number genetic techniques should be able to of genetic "false-positive" cases (those identifl increasingly homogeneous with genetic liability factors who do not groups, leading to increased accuracy of commit antisocial acts) would also exist. behavioral prediction and perhaps ulti- In fact, in any population with a low mately to the clinical ability to quantify base rate of antisocial behavior, reliance risk of certain behaviors, and thus the on genetic predictors would simultane- ability to stratify the population into ously miss most predisposed individuals

Bull Am Acad Psychiatry Law, Vol. 22, No. 3,1994 337 Dinwiddie while overpredicting those at risk for wrongful c~nduct.'~.90 As other biolog- such behavior-the same situation, in ical factors influencing (or potentially other words, that exists now with clinical influencing) the occurrence of socially ability to predict ~iolence.~'," Nonethe- proscribed behaviors become better de- less, the prospect of a simple, "scientific" scribed, it is likely that they will be in- test for liability to future antisocial be- voked in the courtroom as causative of havior might prove attractive to those the wrongful behavior, and hence excul- charged with protecting society, e.g., patory. Once again, the forensic clini- prosecutors faced with dispositional cian may be uniquely equipped to weigh questions such as whether to grant or the scientific evidence, avoiding such ov- revoke parole or probation, whether to ersimplification, and apply it to the legal try a violent offender as a juvenile or an and moral issue of criminal responsibil- adult, whether to seek the death penalty, ity. or similar issues that might hinge on a More generally, the prospect of ge- prediction of future criminal activity. netic testing for liability to antisocial Should specific genetic associations with behavior raises a number of questions violent or otherwise antisocial behavior regarding issues of privacy and freedom be discovered, the forensic clinician may of choi~e.~'If a group with elevated pro- be the only resource available to the pensity to crime becomes identifiable court able to assess critically the impli- through such testing, to what extent (if cations of such research, including the any) should individual rights give way potential errors of classification that to efforts aimed at protecting society? may occur when applying the results of Does widespread testing make sense if such tests to individuals ascertained no preventative intervention is known through the legal system. to work (or is cost-ef'fective)? If effective Another question that could be influ- interventions became available, would enced by deeper understanding of the that justify testing on a voluntary basis? role of genetic factors in antisocial be- Given the cost to society of antisocial havior is the issue of the insanity de- behavior, could it justify involuntary fense. Should such factors become better testing or forcing those at risk to accept characterized, the question of whether treatment? As the biological underpin- and to what extent such factors "caused" nings of repetitive antisocial behavior the unlawful behavior or permitted it to are more precisely characterized, such occur will undoubtedly be debated in issues will assume greater importance. the legal setting. Similar questions about biological determinants of behavior Conclusions have already been raised when experts ASPD, depending on the criteria used have been asked to relate the relevance to diagnose it, occurs in approximately of abnormal findings from neuropsycho- 2 percent to 7 percent of men and 0.5 logical or studies to the percent to 1 percent of women on a defendant's ability to refrain from lifetime Likewise, criminal be-

338 Bull Am Acad Psychiatry Law, Vol. 22, No. 3, 1994 Psychiatric Genetics and Forensic Psychiatry havior is not evenly distributed among posure to environmental risk factors. the general population; it has been esti- From a research perspective, such ad- mated that six percent of offenders are vances hold great promise in early iden- responsible for more than half of police tification, and ultimately perhaps even contacts.92Thus, from a standpoint of prevention or treatment of behaviors public policy, it seems appropriate to that heretofore have proven to be quite study such persistent offenders so that resistant to intervention. the causes of antisocial behavior can be However, such advances in knowledge better understood. have already begun to present ethical Such study, using a variety of meth- issues that will continue to grow in sig- ods, has demonstrated the existence of nificance as more is learned. Oversim- associated familial, heritable factors.13A plification of complex gene-environ- variety of neurochemical and physiolog- ment interactions may lead to inaccu- ical markers associated with antisocial rate labeling of individuals as prone to behavior have also been identified. criminal or violent behavior; even if ac- Thus, as for other complex, common curate, the harm to those so identified syndromes, converging lines of evidence may outweigh any potential good to so- indicate the presence of biological fac- ciety. Conversely, evidence of genetic tors relevant to the development of the markers indicative of heightened liabil- phenotype of antisocial behavior, factors ity to antisocial behavior may be pre- that may themselves be under substan- ferred as an excuse for wrongful behav- tial genetic control. ior. As more is learned of genetic influ- Behavioral genetic studies not only ences on antisocial behavior, the need demonstrate the presence of heritable for informed clinicians able to relate factors, however; they are also necessary these research findings to forensic issues . . in order to understand the role of envi- will continue to grow, - . .- , ,,- A- ronmental factors (particularly those not Acknowledgment shared by siblings) in the genesis of psy- The author thanks Luis Gu&, M.D., Ph.D., Theo- dore Reich, M.D., and Sean Yutzy, M.D., for their chopathology and antisocial behavior.93 comment. on an earlier version of this article. Further advances in our understand- ing of antisocial behavior are likely to References come from a more detailed understand- Cotton NS: The familial incidence of alco- ing at the level of molecular genetics of holism. J Stud Alcohol 40:89-116, 1979 the processes mediating learning and Dinwiddie SH, Cloninger CR: Family and adoption studies in alcoholism and drug ad- temperament, as well a.how such learn- diction. Psychiatric Annals 2 l:206-14, 199 1 ing styles themselves might influence Rice JP, McGuffin P: Genetic etiology of later behavior. Much remains to be schizophrenia and affective disorders, Psy- chiatry, Vol. 1. Edited by Michels R, Cavenar learned as well about how expression of JO. New York: JP Lippincott, Chap 62, pp. inborn factors is influenced by specific 1-24, 1985 Moldin SO, Reich T, Rice JP: Current per- postnatal experiences, and in what way spectives on the genetics of unipolar depres- genetic factors may influence later ex- sion. Behav Genet 21:211-42, 1991

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