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Probing the Nature of Child Psychopathology
GENETIC CONTRIBUTIONS TO EARLY-ONSET PSYCHOPATHOLOGY
1056-4993/01 $15.00 + .00
PROBING THE NATURE OF CHILD PSYCHOPATHOLOGY Richard D. Todd, PhD, MD
Any serious consideration of the ongms of child and adolescent psychopathology must begin with an evolutionary perspective of our genetic and cultural heritages.9• 11 • 31 Genetic programming does not begin with conception, nor does social development begin with mother- child bonding. Today's "nature" and "nurture" are the results of long-term processes. Similarly, the current geographic distributions of DNA variations and cultural attitudes reflect the effects of long-term processes. Although the clinician's traditional unit of attention or measurement is the child within his or her family, our fundamental starting point in understanding the nature or etiology of our clinical syndromes should be the interaction of genes, environment, and time. This view is of course not restricted to the consideration of disease but also applies to analyses of almost all components of behavior and biology. For example, a variety of recent articles have suggested that the basic biologic clock (or pacemaker) that drives the circadian wake-sleep cycle of behavior is under similar genetic control in cyanobacteria, plants, flies, and mammals.35 The basic sleep-wake cycle of man averages about 25 hours but is "reset" daily by external cues. If individuals are removed from external time cues, then an individual quickly reverts to his or her internal pacemaker for sleep-wake cycle length. This periodicity is governed by the production of transcription factors that secondarily regulate the expression of a variety of genes. Although the basic This work was supported by grants MH 52813 and MH 31302 and the lttleson Endowment Fund.
From the Division of Child and Adolescent Psychiatry, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 10 • NUMBER 2 • APRIL 2001
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molecular machinery of this clock is complex and involves the interaction of a variety of proteins, single amino acid changes in several of these genes have been identified that change the periodicity of the clock by several hours. Thus, there is overwhelming evidence that circadian rhythms are regulated by specific genetic pathways. The length of the basic cycle period, however, cannot have been constant over evolutionary time periods. The basic circadian rhythm, which is slightly more than 24 hours in most species, closely matches our current earth's day/ night cycle (due to rotation around its north/south axis). Over the past few billion years, however, this rate of rotation has decreased from about 15 hours to the current 24 hours. Because it is unlikely that the current endogenous circadian clock of most organisms serendipitously matches the current rotation period of the earth, the genetic mechanisms that control the circadian rhythm (which are evolutionarily old) must have evolved to match the current rate of rotation of the earth as it slowed over the past few billion years. The thesis of this article is that even though we treat individual children or their families, grounding our research in an evolutionary and epidemiologic framework advances our understanding of the structure of psychopathology. I present one perspective on the nature of child psychopathology and explore the implications of such a perspective for both research and practice. In this article data are drawn from behavioral genetic analyses of several normal and abnormal behaviors. Although behavioral genetic approaches are usually thought of as giving a measure of heritability (the genetic contribution to a given disorder), the real goal of such an approach is to explain individual variation given a particular set of genes and environments.17 In many ways, such genetically informative, family-based designs represent the most serious approach to the study of environment by allowing a natural scalar for controlling for potential genetic contributions to risk. Such family-based research designs can also powerfully address a variety of clinically relevant issues, including the effects of different informants, the effects of gender, the effects of ethnicity, and the effects of comorbidity on disease expression. 32 Before exploring what is the structure of psychopathology, it is important to review several basic concepts. SYNDROMES, DISEASES, CATEGORIES, AND CONTINUA
Although it is convenient to think of diseases as being discrete entities with discrete identifiable etiologies, many well-defined disorders are extremes of continua in which clinical caseness is statistical in nature. For example, the distribution of diastolic blood pressure in the general population shows no distinct categories or groups even though we know that very high or very low diastolic blood pressures are associated with serious clinical consequences. The current guidelines for saying who is hypertensive or hypotensive are based on statistical criteria that aim to
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minimize both the negative consequences of extremes of blood pressure as well as the potential negative consequences of treatment. The majority of our diagnoses for psychiatric problems, as codified in the Diagnostic and Statistical Manual (DSM-IV) or the International Classification of Disease (ICD-10), are categoric (one does or does not have the condition). Because in general we lack discrete etiologic factors of overwhelming importance for our diagnoses, most psychiatric diagnoses are also syndromatic in nature. That is, our diagnoses are collections of signs and symptoms that occur more frequently in individuals than would be expected based on the prevalences of these signs and symptoms in the general population. This concept of a syndrome is both epidemiologic and statistical. Hence, to make the majority of our diagnoses, we require epidemiologic information on the occurrence of both individual signs and symptoms as well as their co-occurrence within individuals. Of course this is problematic for our field because the estimates of the prevalence of most child or adolescent syndromes, signs, or symptoms in the general population have poor accuracy. In general, we also lack sufficient data to test critically whether disorders are discrete or are extremes of continua. Such problems with epidemiologic accuracy may not be so problematic for rare serious disorders such as autism, but as we argue, even in such uncommon disorders a lack of systematic information from large population samples may result in misconceptions about the underlying nature of such disorders. Researchers in child psychopathology usually lament that they cannot apply the same rigorous definition of disease to syndromes as can be done in other branches of medicine. This should not be misconstrued, however, as being due to fundamental differences in the nature of our disorders but should be looked at as a problem of the difficulty we have in measurement and experimental design. We note that similar problems directly confronted our colleagues in other fields such as infectious disease. For example, the time-tested postulates of Koch with respect to the necessary and sufficient conditions for developing a disease of infectious origin cannot be applied to many of the infectious agents or suspected infectious disorders that are of concern to us today. For many viruses and bacteria thought to be important in different disorders, there are no appropriate laboratory models for passage of the organism or for demonstrating infectivity, nor are there sensitive tests for the detection of the organism in all cases of the disorder. This has led to a relaxation of the clear-cut criteria of 18th-century German medicine to an epidemiologic- and statistical-based definition of disease even when the causative agent is thought to be known. As discussed previously, the concept of discrete diseases or disorders is frequently inappropriate. For many common entities there is no clear-cut distinction between who is affected or unaffected in the general population. The above discussion of blood pressure also can be applied to levels of glucose or cholesterol and associated disorders. Although it is true that particular genetic factors can be associated with "familial" cases of hypercholesterolemia19 or diabetes mellitus, 2• 24 such discrete
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factors account for a small percentage of the variance of serum cholesterol or glucose levels in the general population.
FAMILIALITY AND HERITABILITY
As outlined by Robins and Guze,27 one of the often-used criteria for the validity of a given diagnosis is familial specificity. By this we mean that the prevalence of a given diagnosis among family members is higher than in the general population and is also higher than other unrelated diagnoses. That is, the concordance rate among family members is higher than the prevalence of the disorder in the general population. In its most general form, such family concordance may be among biologic or adoptive relatives. As with the definition of a syndrome or disease, the definition of familiality is epidemiologic and statistical in nature, as one must have an estimate of the prevalence of illness among both the relatives of the proband (the individual who brings the family to attention) and the general population. This may be estimated by several types of family designs (Figs. 1 and 2). Such familiality may be caused by environmental factors such as a common cultural context or common exposure to specific traumatic events, genetic factors, and so forth. Whatever the origin of familiality, the etiologically significant
Figure 1. Four examples of family-based research designs traditionally used for the elucidation of factors contributing to disease etiology. In all figures a solid symbol represents a case, and an open symbol represents a control or unknown phenotype status for an individual. Squares represent men, and circles represent women. A, The traditional and most widely used design is the case-control design, in which no information is considered from family members. B, The traditional case-control design is expanded to include family information on closely related relatives. In each case the individual identifying the family (the proband) is indicated by an arrow. C, In the extended family-control design, more distantly related relatives are studied. This includes siblings and cousins, who experience the same cohort or period effects in environment. 32 In this case, individuals who are related to the proband (arrow) and who have the same disorder (solid squares or circles) should be more similar to the proband than those relatives who are not related. Such an extended family design is widely used in linkage studies that identify genetic loci associated with disease; however, this approach is best suited to rare disorders or simple genetics structures (such as an autosomal-dominant or recessive disease). 0, A newer family design (nontransmitted allele control), in which the proband and parents are identified as usual is shown. The control in this case, however, is those portions of the DNA from the parents not transmitted to the affected offspring (arrow). In this example the parents carry different alleles for a specific locus indicated by AB for the father and CD for the mother. The affected child carries the genotype AC for this locus, whereas the nontransmitted alleles are represented by the dotted line to the hypothetical individual with the genotype BO. Under this scenaro, it is assumed that A or C is associated with the disease, and hence BD is not. To test this, the proportion of transmitted versus nontransmitted alleles or genotypes is determined for a large number of families to see if there is enrichment of one allele or genotype.
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factor is shared among relatives. An example of an environmental model for familiality is tuberculosis, in which there is a general increase in exposure to the causative agent among relatives living in close proximity, which is related to the amount of contact between individuals rather than their specific biologic relationship. Other environmental models that incorporate biologic relationships, such as child exposure to particular parenting styles, are plausible but in general are difficult to predict a priori. In contrast, most models of risk due to genetic factors follow specific patterns depending on the nature of the gene-syndrome relationship. This may range from a fully expressed autosomal dominant contribution, which results in half of the offspring of an individual being affected, to complex interactions among several genes and/ or environmental elements. Because in general the distribution of genes between
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1.0/0.5
T1
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T2
Figure 2. In the traditional twin study design, twins are determined to be monozygotic (paternal or identical) or dizygotic (fraternal or nonidentical). Given that one twin is affected with the disorder, the concordance rate is calculated for the second twin as a function of being monozygotic or dizygotic. The goal is to determine how twin-twin similarity varies as a function of degree of genetic relatedness. Higher concordance rates for monozygotic compared with dizygotic twins are compatible with genetic factors being important in disease etiology. For twin studies, similarities or differences can be characterized by three factors 17: (1) additive genetic factors are identical for monozygotic twins but only shared 50% of the time (on average) by dizygotic twins; (2) common environment is by definition shared 100% by twins regardless of zygosity; and (3) unique environment is not correlated between the two twins. It should be noted that unique environment also includes any noncorrelated errors in measurement of the phenotype. A = additive genetic; C = common environment; E = unique environment; T1 = twin 1; T2 = twin 2.
parents and children follows simple rules, it is possible to predict the phenotypic outcomes of a variety of genetic models. A common notation and conceptualization of this principle has been proposed by Risch25 in which a ratio, A.R, is defined by the prevalence of the disorder in a given class of relatives of the proband divided by the prevalence of the disorder in the general population. The behavior of A.R among biologic relatives can be specified for different classes of relatives for a given genetic model without knowing any of the specific gene elements involved. It should be noted, however, that estimates of A.R are no better than the estimates of recurrence risk among family members and estimates of prevalence in the general population. This can be particularly problematic when the diagnosis is a quantitative entity such as hypertension versus a categoric entity. Although it is certainly conceivable that a clever researcher could propose a complex environmental model that would mimic the effects of a given set of A.R ratios, it is difficult to propose such models a priori. Hence, a "relative" risk approach to estimating heritability has the compelling logic of the application of simple genetic rules. What underlies all estimates of heritability is the degree to which
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Table 1. DNA SHARING BY RELATIVES Relative Pair
DNA Shared (% IBD)
Correlation for IQ*
Monozygotic twins Dizygotic twins Siblings Adopted away siblings Parent:child Aunt/ uncle:niece I nephew First cousins Spouses Parent:adopted child
100 50 50 50 50 25 12.5 0 0
0.86 0.60 0.47 0.34 0.42 NR 0.15 0.33 0.19
IBO = identical by descent; NR = not reported. *Data from Bouchard TJ, McGue M: Familial studies of intelligence: A review. Science 212:1055-1059, 1981.
parents and offspring share genes or DNA sequences that are identical by descent (passed from parent to child; see Fig. 1 and Table 1). That is, the offspring receives a set of usually exact copies of parental DNA sequences, which are frequently shuffled by recombination and occasionally changed by mutation. For example, monozygotic twins are 100% identical with each other (see Fig. 2; exceptions are notable but rare). In contrast, dizygotic or fraternal twins are 50% identical by descent (IBD) with each parent and on average are 50% IBD with each other. Similarly, grandparent-grandchild pairs are on average 25% IBD and first cousins are on average 12.5% IBD. These differences in percent IBD of DNA sequences for different classes of relatives form the basis of prediction for genetic models. In the absence of specific information about a causative DNA sequence, these estimates apply only to groups of relatives and, hence, are statistical in nature. It should be kept in mind then that definitions of illness and estimates of familiality, whether environmental or genetic in nature, are probabilistic in nature and therefore are not absolute proof of causation. Lacking identification of specific environmental agents or DNA mutations, we must remain humble in our interpretation of findings of familiality and not come to extreme conclusions that are not warranted by the statistical nature of our evidence. ENVIRONMENT, CULTURE, AND MEASUREMENT ERROR
As described, familiality of illness, which for many childhood-onset disorders appears to be strong, may involve genetic or environmental factors or both. Although one might argue whether two individuals ever experience the same environment, environmental effects are usually parceled into those that are thought to be common to a class of individu-
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als and those thought to be unique to a given individual (or uncorrelated among a class of individuals). Common environmental influences may range from nuclear family factors such as parenting style to group factors such as religious or cultural orientation to factors that influence large segments of the population, such as war, famine, disease, or social revolution. Indeed, evolutionary biologists have frequently invoked common environmental factors such as climactic change or widespread famine as being the cause of genetic or cultural bottlenecks by elimination of large segments of the population. On a more microcosmic level, common environmental factors may be peer-group influences or socioeconomic factors. In contrast, unique environmental factors are those experiences that are different for different members of a sibship or a group of family members. They may involve unique insults, such as injury or illness, or may be due to different cultural factors that act as a function of age on a given individual. This latter mechanism, which cannot account for differences among twins (who are the same age), may be important in differences among nontwin siblings. Similarly, sexbased environmental differences, which may affect boys and girls as classes, are unique environmental experiences for opposite sex twin pairs and opposite sex nontwin siblings. Although these examples of distinctions between shared and unique environment are commonly appreciated, it must be emphasized that random errors in measurement between individuals are uncorrelated and will be parceled out as unique environmental experience. Hence, although much has been made about the relatively large estimates of a unique environment compared to a common environment for many behaviors and symptoms of relevance to child psychopathology,22 many studies either have measurement errors of similar magnitude to unique environment estimates or have no stated measurement error estimates at all. The effect of random errors in measurement is to decrease the magnitude of estimates of both genetic and common environmental factors. From this point of view, measured values of the contributions of genetic and common environmental factors should be viewed as minimal estimates. An underlying assumption of most studies of family resemblance (whether investigating genetic or shared family environment effects) is that parents have mated at random with respect to the characteristics under study. It is quite clear that individuals in marriages or other unions that produce offspring have not randomly chosen one another because there are on average marked similarities in age, socioeconomic status, religion, race/ ethnicity, and so forth among mothers and fathers. Whether such so-called "assortative" mating includes biases in reproduction based on psychiatric status is less clear. As reviewed recently by Maes et al,14 a number of studies have found evidence for marital resemblance for both psychiatric disorders and combinations of psychiatric disorders. In an analysis of two large population-based twin samples, Maes et al14 did find a moderate degree of assortative mating both within and across psychiatric disorders. This was on the order of 0% to
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20%. Only a small amount of the observed assortative mating could be explained by correlated variables such as age, education, or religious attendance. Su ch assortative mating would tend to increase estimates of a shared common environment and decreased estimates of genetic factors in twin studies; however, simulations 14 suggest that such effects would be minimal secondary to the modest degree of observed assortative mating.
GENETIC BASIS OF ANIMAL BEHAVIOR
As outlined by Plomin, 22 applied behavioral genetics has existed for thousands of years in the domestication of animals for both morphologic and behavioral characteristics. This can be easily observed by a visit to any dog breeder or humane society facility, where the animal handlers can reliably predict the adult size, the expected aggressivity, and the degree of intelligence of individual pure-bred and mixed-breed puppies. Breeds such as pitbulls are known for aggressive/territorial behavior, whereas breeds such as Australian shepherds are known for intelligence, trainability, and herding instincts. Similarly, a variety of behaviorally distinct laboratory animal strains have been inbred for multiple generations by selecting for a variety of behavioral characteristics ranging from the ability to perform maze tests to the degree of alcohol or nicotine ingestion. The results of such animal-breeding experiments (which mimic the evolutionary selection of traits in nature) have several implications for studies of child and adolescent psychopathology. First, for both simple and complex behaviors, it is easy to demonstrate the existence of genetic contributions to behavior. Second, the overall heritability estimates for behaviors selected for in this fashion are usually less than 50%. That is, most of the familiality of a specific behavior is not genetic in origin but is due to environmental factors. Finally, for the majority of selected behavioral traits, the genetic structure is complex and appears to involve many genes. Although many strains that have been developed by planned mutagenesis or by capitalizing on spontaneous mutations have extreme single-gene phenotypes reminiscent of Mendelian disorders, the normal range of behavioral variability found in these inbred strains cannot be accounted for by the effects of a few genes. To the extent we determine that child and adolescent psychopathologic disorders are best viewed as extremes of normal variation in behavior, then by analogy with animal-breeding experiments we can expect that these behaviors will involve the influence of a variety of genes and that the magnitude of genetic effects will in general not exceed 50% of the explainable variance. This of course implies there may be important environmental intervention points in modifying or preventing the expression of deleterious gene effects without requiring direct gene therapy interventions. The classic example of this is phenylketonuria, an autosomal-recessive disorder, in which elimination of phenylalanine from the
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diet from early in life minimizes the developmental effects of mutations in the phenylalanine hydroxylase gene. ENVIRONMENTAL BASIS OF ANIMAL BEHAVIOR
A major theme of developmental theory in psychology has been that early experiences disproportionally influence human adult behavior. This notion has been difficult to document at the human level secondary to ethical considerations of experimental design; however, as reviewed by Suomi,30 there is compelling evidence for such long-lasting influences of early environmental experience in animal studies. In particular, studies of rhesus monkeys have demonstrated the importance of early social relationships with caregivers for behavioral and physiologic characteristics throughout life. For example, different rearing circumstances (both with respect to the type of caregiver and the size of the social group) affect the expected increase in plasma cortisol in response to the stress of short-term isolation. 28 Individual behavioral differences in rhesus monkeys, which may be due to either genetic differences or early rearing experiences, may also be overwhelmed by extreme environmental stressors later in life. 10 For these behavioral and physiologic effects, however, the true situation is likely to include both important environmental and genetic components. For example, a variety of human and primate studies have demonstrated an inverse relationship between certain types of aggressive or self-injurious behavior and cerebral spinal fluid serotonin metabolite levels. Recent primate work has also demonstrated important species and inter-individual differences in serotonin metabolite levels, which correlate positively with social position and inversely with aggression.4' 34 These metabolite levels are not static and can change with environmental manipulations such as alterations in the social hierarchy of a troop. In contrast, Clarke et al5 have presented evidence that basal serotonin and other monoamine metabolite levels in the cerebral spinal fluid of rhesus monkeys are under genetic control. As suggested by Clarke et al,5 studies incorporating both genetic and environment factors are likely to be more productive in understanding normal behaviors and vulnerability to psychopathology. GENETICS AND NORMAL HUMAN BEHAVIOR
Before discussing the importance of and mechanisms of contribution of genetic factors to child and adolescent psychopathology, it is important to remember that a variety of normal human behaviors and abilities appear to be under significant genetic control. The example of circadian rhythm was discussed previously. Similarly, a variety of troubling but nonpathologic childhood behaviors such as enuresis, sleep walking, nail biting, or thumb sucking have significant heritabilities in
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the range of 0.3 to 1.0. 16 Similarly, a variety of twin and adoption studies have estimated the genetic contributions to personality/temperament features to be on the order of 30% to 50%.20, 29 Perhaps the best-studied "normal" behavior trait in humans is general cognitive ability (so-called IQ). In a massive compilation of more than 100 family studies of intelligence, Bouchard and McGue 3 found a marked correlation of IQ scores with the percent DNA shared identical by descent for various classes of relatives (see Table 1). For example, the overall correlation from monozygotic twins was 0.86, whereas the overall correlation of dizygotic twins was 0.60, which is compatible with a broad heritability of about 50%. At the same time, however, there was evidence for assortative mating because the correlation for biologically unrelated spouses was about 33%. Other environmental effects are also likely because although the correlation among nontwin siblings was 0.47, this correlation dropped to 0.34 for adopted-away siblings. This is in keeping with newer studies estimating the heritability of IQ, which suggests that overall the heritability for general cognitive ability is about 50%. The estimated errors were thought to be on the order of 20% across these studies, suggesting that the true heritability of our general cognitive ability is somewhere between 30% and 70%. In particular, Plomin has investigated cognitive ability as a function of age.23 These studies have been illuminating in that from infancy to early school years estimates of the heritability of IQ increase and appear to be highly correlated with genetic effects of IQ in adulthood. Recently, this has been extended to elderly twin pairs demonstrating persistent genetic effects on IQ even though the magnitude of their unique environmental experience has presumably increased over the course of their lifetime. This brief summary of both animal breeding and human family studies regarding normal behavioral traits suggests that many of the symptom domains that are found to be involved in psychopathologic states are under marked genetic control in the general population and that the underlying basis of this control is the action of multiple genes for each trait. This is compatible with the recognized continuous distributions of trait attributes in the normal population and, as will be discussed next, has implications for the nature of psychopathologic disorders. WHAT IS THE STRUCTURE OF CHILD AND ADOLESCENT DISORDERS?
As outlined herein, to investigate the etiology of psychopathologic disorders, one needs to take an evolutionary and epidemiologic perspective. Unfortunately, few of our disorders have sufficient epidemiologic data on the presence of individual or groups of psychiatric symptoms to allow critical tests of the structure of disorders. Similarly, we lack sufficient knowledge of the environmental context of symptoms over evolutionary time periods to gauge whether today's problem behaviors
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were advantageous or neutral in the past.31 In particular, we lack sufficient data to determine whether symptom domains represent discrete disorders, discrete continua, or some mixture of categoric and continuum entities. Similarly, whether the observed comorbidities (that is, the presence of two or more diagnostic entities in the same individual) reflect the familial aggregation of different illnesses via mechanisms such as assortative mating or reflect distinct genetic subtypes of disorders is also unclear. These problems and their subsequent impact on the diagnosis, treatment, or investigation of our clinical entities are highlighted by the examples of autism and attention-deficit/hyperactivity disorder (ADHD). These two examples are chosen secondary to their reported differences in prevalence and morbidity. Autism is thought to be a rare and severe early-onset disorder characterized by (1) qualitative impairments in social interactions, (2) communication deficits, and (3) restricted, repetitive, and stereotypical patterns of behavior, interest, and activities (DSM-IV). Other related pervasive developmental disorders share deficits in social interactions but have variable presence of the other features of autism. A variety of twin and family studies of categorically defined illness have demonstrated that autism is largely genetically determined.1 Interestingly, twin and family studies have also shown that the abnormal social behaviors characteristic of autism significantly aggregate in family members of autistic probands.12• 21• 36 Strikingly, no population-based studies have been reported regarding the prevalence of individual autism symptoms or groups of symptoms in the general population. In the course of developing a screening instrument for the identification of pervasive developmental disorder cases for use by parents and schoolteachers, we unexpectedly found a continuous distribution of endorsement of social interaction symptoms in a random sample of students.6 A significant fraction of these students received symptom scores overlapping with a clinic-based group of autistic and pervasive developmental disorder patients. That is, the clinic cases were at the high end of the distribution of scores in this instrument, but there was no clear dividing line between the scores of school children and clinical cases. A variety of clustering procedures was compatible, with problems of social interaction being a continuous variable in this population. This questionnaire was then completed by a parent for more than 200 male:male twin pairs aged 9 to 14 years as identified through birth records of the state of Missouri. Once again, in this population-based sample of twins, social interaction problem scores appear continuously distributed. Monozygotic twin pairs had significantly higher correlations for scores than dizygotic twin pairs, which is consistent with the involvement of genes for this characteristic. More formal twin analysis estimated the heritability of scale scores to be 75% with no evidence for common environment contributions to family resemblance. 6• The results of these two studies taken together with previous twin and family studies of autism suggest that at least one of the core features of autism (problems
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with social interactions) may be continuously distributed in the population and that families of autistic individuals lie at one extreme end of this continuum. Given both the reported high heritabilities of autism and our estimates of the heritability of social problems in the general population it is possible that autism is not a rare categoric disorder as described in DSM-IV but is the extreme end of a population distribution with no clear division between affected and unaffected status. This concept is compatible with the results of recent studies trying to identify genes for autism that suggest that a large number of genetic loci are likely to be involved in categorically defined cases of autism. 26 In contrast to autism, ADHD is thought to be common and although associated with impairments in school, peer, or home functioning is clearly not as incapacitating as autism (DSM-IV). A variety of twin studies (whether of categoric diagnoses, symptom counts, or scale measures) are compatible with autism having a heritability in the range of 0.6 to 0.9.7 Under DSM-IV criteria ADHD occurs in three mutually exclusive subtypes referred to as inattentive, hyperactive/impulsive, and combined. Little data have been reported on the relative heritabilities of these DSM-IV subtypes, but a number of studies have attempted to look independently at the heritability of inattentive and hyperactive/ impulsive symptoms. 33 Based on such analyses, several investigators have suggested that ADHD is best viewed as a continuum of problems with inattentive and hyperactive/impulsive symptoms. 8, 13 We have attempted to test formally whether ADHD is best conceived of as a categoric or continuum disorder by the application of parametric and nonparametric clustering procedures to DSM-IV ADHD symptom data reported by parents on their children (Todd RD, Neuman RJ, Reich W, et al: submitted for publication). 8 ' 18, 18• Our initial results based on a sample of approximately 1500 female twin pairs identified from birth records of the state of Missouri were interpreted as supporting a continuum position, 8 in which there were separate continua for inattention problems, hyperactive/impulsive problems, and combined subtype problems. Similar results were found for both boys and girls in a sample of families identified through alcoholic probands. 18 Further analyses on an enlarged sample of more than 2000 female twin pairs, however, support a different model. 18• In a continuum model, twins in the same twin pair would be expected to lie along the same portion of the continuum but not necessarily at the same point. In contrast, if the apparent continuum is represented by multiple independent types of ADHD, then twin pair members would be expected to have the same type of ADHD. Analysis of within and between twin pair phenotypes using a clustering procedure referred to as latent class analysis 15 is most compatible, with multiple genetically independent forms of ADHD in this general population sample of female twins (Todd RD, Neuman RJ, Reich W, et al: submitted for publication).
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In both of these examples, careful attention to the collection and interpretation of population-based data results in models that challenge current views of the structure of these two psychopathologic conditions. For autism, it is suggested that caseness represents the end of a distribution of deviance in the general population. In contrast, for ADHD there may be multiple genetically independent forms of ADHD in the general population, which only partially overlap with DSM-IV conceptualizations of illness. Both these findings have implications for study designs aimed at identifying genetic factors involved in these illnesses and for clinical practice. First, current estimates of the multi-locus etiology of autism suggest that sufficient multiplex autism families may not exist to allow the definition of the responsible DNA elements. An alternative strategy for the identification of these genetic elements, however, would be to take sibling pairs from the general population who differ on quantitative measures of social interaction problems (a discordant quantitative trait locus [QTL] design). Specific associations found in such general population studies could then be secondarily tested in singleton and multiplex autism families. Similarly for ADHD, linkage analysis of extended pedigrees may be inappropriate. First, if ADHD is in fact composed of multiple genetically independent forms of ADHD, the use of extended families is likely to introduce genetic heterogeneity within single pedigrees. This greatly increases the difficulty of identifying susceptibility loci. Similarly, the use of DSM-IV ADHD subtypes for analysis would likely decrease the power of studies due to the mixing of different independently heritable subtypes. In the case of ADHD it may be more cost effective to focus on nuclear families with particular heritable subtypes identified through population samples as described earlier. With respect to the clinical problems of who and when to treat, the results of the earlier discussions suggest these will be different for autism and ADHD. The presence of multiple genetically independent forms of ADHD may suggest specific treatments for individual subtypes. Hence, in the future it may be possible to direct pharmacologic or behavioral treatments for ADHD based on either clinical or genotype information. For autism, if the true underlying problems represent a continuum, then the decision to call an individual affected or not must include riskbenefit analyses of individual treatments because the conceptualization of caseness is arbitrary. CONCLUSIONS
As outlined in this article, studying the etiology of child and adolescent psychopathology may require establishing an evolutionary and epidemiologic context. Although increases in our understanding of past environmental pressures and history over evolutionary time periods may be limited by a fragmented historic record, we can make advancements in understanding the epidemiology and significance of individual symptoms and groups of symptoms to best determine the underlying
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structure of psychopathology. By placing nosologic or etiologic studies in a family/ genetic design, the relative magnitude of both environmental and genetic effects (and possible interactions among these) can be determined while controlling in a natural way for a variety of potential confounding variables. In particular, the application of such techniques may help determine the true underlying structures of psychiatric disorders and enhance the ability to identify mutations or allelic DNA sequence differences contributing to psychopathology. It is hoped that defining DNA variations contributing to psychopathology will enhance the power of treatment studies whether they are of behavioral, pharmacologic, or other substance. ACKNOWLEDGMENTS The author thanks his colleagues and the families who have participated in the studies described in this article and John Constantino, MD, for commenting on an earlier draft of the manuscript.
References 1. Bailey A, LeCoutteur A, Gottesman I, et al: Autism as a strongly genetic disorder: Evidence from a British twin study. Psychol Med 25:63-77, 1995 2. Bell BI, Pilkis SJ, Weber IT, et al: Glucokinase mutations, insulin secretion, and diabetes mellitus. Ann Rev Physiology 58:171- 186, 1996 3. Bouchard TJ, McGue M: Familial studies of intelligence: A review. Science 212:10551059, 1981 4. Champoux M, Higley JD, Suomi SJ: Behavioral and physiological characteristics of Indian and Chinese-Indian hybrid rhesus infants. Dev Psychobiol 31:49-63, 1997 5. Clarke AS, Kammerer CM, George KP, et al: Evidence for heritability of biogenic amine levels in the cerebrospinal fluid of rhesus monkeys. Biol Psychiatry 38:572577, 1995 6. Constantino JN, Przybeck T, Friesen D, et al: Reciprocal social behavior in children with and without pervasive developmental disorders. J Dev Behav Pediatr 21:2-11, 2000 6a. Constantino JN, Todd RD: Genetic structure of reciprocal social behavior. Am J Psychiatry 157:2043- 2045, 2000 7. Faraone SV, Biederman J: Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 44:951-958, 1998 8. Hudziak JJ, Heath AC, Madden PF, et al: Latent class and factor analysis of DSM-IV ADHD: A twin study of female adolescents. J Am Acad Child Adolesc Psychiatry 37:848- 857, 1998 9. Jensen PS, Mrazek D, Knapp PK, et al: Evolution and revolution in child psychiatry: ADHD as a disorder of adaptation. J Am Acad Child Adolescent Psychiatry 36:16721681, 1997 10. Lauadenslager ML, Rasmussen KL, Berman CM, et al: A preliminary description of responses of free-ranging rhesus monkeys to brief capture experiences: Behavior, endocrine, immune and health relationships. Brain Behav Immunol 13:124-137, 1999 11. Leckman JF, Mayes LC: Understanding developmental psychopathology: How useful are evolutionary accounts. J Am Acad Child Adolesc Psychiatry 37:1011-1021, 1998 12. LeCoutteur A, Bailey A, Goode S, et al: A broader phenotype of autism: The clinical spectrum in twins. J Child Psychol Psychiatry 37:785-801, 1996 13. Levy F, Hay D, McStephen M, Wood C, et al: Attention-deficit hyperactivity disorder: A category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry 36:737- 744, 1997
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14. Maes HHM, Neale MC, Kendler KS, et al: Assortative mating for major psychiatric diagnoses in two population-based samples. Psycho! Med 28:1389-1401, 1998 15. McCutcheon AL: Latent Class Analysis. Newbury Park, CA, Sage, 1987 16. McGuffin P, Gottesman I: Genetic influences on normal and abnormal development. In Rutter M, Hersov L (eds): Child and Adolescent Psychiatry: Modern Approaches, ed 2. Oxford, Blackwell Scientific Publications, 1985, pp 17-33 17. Neale MC, Cardon LR: Methodology for genetic studies of twins and families. Boston, Kluwer Academic, 1992 18. Neuman RJ, Todd RD, Heath AC, et al: The evaluation of ADHD typology in three contrasting samples: A latent class approach. J Am Acad Child Adolesc Psychiatry 38:25-33, 1999 18a. Neuman RJ, Heath AC, Hudziak JJ, et al: Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins. J Child Psycho! Psychiatry, in press 19. Ose L: An update on familial hypercholesterolaemia. Ann Med 31:13-18, 1999 20. Parker G: Special feature: The etiology of personality disorders: A review and consideration of research models. J Personality Dis 11:345-369, 1997 21. Piven J, Palmer P, Jacobbi D, et al: Broader autism phenotype: Evidence from a family history study of multiple-incidence autism families. Am J Psychiatry 154:185-190, 1997 22. Plomin R: The role of inheritance in behavior. Science 248:183-188, 1990 23. Plomin R: Genetics and general cognitive ability. Nature 402:C25-29, 1999 24. Polansky KS, Sturis J, Bell GI: Seminars in medicine of the Beth Israel Hospital, Boston: Non-insulin-dependent diabetes mellitus-a genetically programmed failure of the beta cell to compensate for insulin resistance. New Engl J Med 334:777-783, 1996 25. Risch N: Linkage strategies for genetically complex traits: I. Multilocus models. Am J Hum Genet 46:222-228, 1990 26. Risch N, Spiker D, Lotspeich L, et al: A genomic screen of autism for a multilocus etiology. Am J Hum Genet 65:493-507, 1999 27. Robins E, Guze S: Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. Am J Psychiatry 126:107-111, 1990 28. Shannon C, Champoux M, Suomi SJ: Rearing condition and plasma cortisol in rhesus monkey infants. Am J Primatol 46:311-321, 1998 29. Stallings MC, Hewitt JK, Cloninger CR, et al: Genetic and environmental structure of the Tridimensional Personality Questionnaire: Three or four temperament dimensions? J Pers Soc Psycho! 70:127-140, 1996 30. Suomi SJ: Early determinants of behaviour: Evidence from primate studies [review]. Br Med Bull 53:170-184, 1997 31. Thornhill R, Moller AP: Developmental stability, disease and medicine. Biol Rev Camb Philos Soc 72:497-548, 1997 32. Todd R: Use of siblings, twins, and cousins in the study of child and adolescent psychopathology. Curr Opin Psychiatry 7:315-318, 1994 33. Todd RD: Genetics of attention deficit/ hyperactivity disorder: Are we ready for molecular genetic studies? Am J Med Genet 91:000-000, 2000 34. Westergaard GC, Suomi SJ, Higley JD, et al: CSF 5-HIAA and aggression in female macaque monkeys: Species and interindividual differences. Psychopharmacology 146:440-446, 1999 35. Wilsbacher LD, Takahashi JS: Circadian rhythms: Molecular basis of the clock. Curr Opin Genet Dev 8:595-602, 1988 36. Wolff S, Narayan S, Moyes B: Personality characteristics of parents of autistic children. J Child Psychol Psychiatry 29:143- 153, 1988
Address reprint requests to Richard D. Todd, PhD, MD Department of Psychiatry, Box 8134 Washington University School of Medicine 660 South Euclid Avenue St. Louis, MO 63110
1056-4993/01 $15.00 + .00
PROBING THE NATURE OF CHILD PSYCHOPATHOLOGY Richard D. Todd, PhD, MD
Any serious consideration of the ongms of child and adolescent psychopathology must begin with an evolutionary perspective of our genetic and cultural heritages.9• 11 • 31 Genetic programming does not begin with conception, nor does social development begin with mother- child bonding. Today's "nature" and "nurture" are the results of long-term processes. Similarly, the current geographic distributions of DNA variations and cultural attitudes reflect the effects of long-term processes. Although the clinician's traditional unit of attention or measurement is the child within his or her family, our fundamental starting point in understanding the nature or etiology of our clinical syndromes should be the interaction of genes, environment, and time. This view is of course not restricted to the consideration of disease but also applies to analyses of almost all components of behavior and biology. For example, a variety of recent articles have suggested that the basic biologic clock (or pacemaker) that drives the circadian wake-sleep cycle of behavior is under similar genetic control in cyanobacteria, plants, flies, and mammals.35 The basic sleep-wake cycle of man averages about 25 hours but is "reset" daily by external cues. If individuals are removed from external time cues, then an individual quickly reverts to his or her internal pacemaker for sleep-wake cycle length. This periodicity is governed by the production of transcription factors that secondarily regulate the expression of a variety of genes. Although the basic This work was supported by grants MH 52813 and MH 31302 and the lttleson Endowment Fund.
From the Division of Child and Adolescent Psychiatry, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 10 • NUMBER 2 • APRIL 2001
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molecular machinery of this clock is complex and involves the interaction of a variety of proteins, single amino acid changes in several of these genes have been identified that change the periodicity of the clock by several hours. Thus, there is overwhelming evidence that circadian rhythms are regulated by specific genetic pathways. The length of the basic cycle period, however, cannot have been constant over evolutionary time periods. The basic circadian rhythm, which is slightly more than 24 hours in most species, closely matches our current earth's day/ night cycle (due to rotation around its north/south axis). Over the past few billion years, however, this rate of rotation has decreased from about 15 hours to the current 24 hours. Because it is unlikely that the current endogenous circadian clock of most organisms serendipitously matches the current rotation period of the earth, the genetic mechanisms that control the circadian rhythm (which are evolutionarily old) must have evolved to match the current rate of rotation of the earth as it slowed over the past few billion years. The thesis of this article is that even though we treat individual children or their families, grounding our research in an evolutionary and epidemiologic framework advances our understanding of the structure of psychopathology. I present one perspective on the nature of child psychopathology and explore the implications of such a perspective for both research and practice. In this article data are drawn from behavioral genetic analyses of several normal and abnormal behaviors. Although behavioral genetic approaches are usually thought of as giving a measure of heritability (the genetic contribution to a given disorder), the real goal of such an approach is to explain individual variation given a particular set of genes and environments.17 In many ways, such genetically informative, family-based designs represent the most serious approach to the study of environment by allowing a natural scalar for controlling for potential genetic contributions to risk. Such family-based research designs can also powerfully address a variety of clinically relevant issues, including the effects of different informants, the effects of gender, the effects of ethnicity, and the effects of comorbidity on disease expression. 32 Before exploring what is the structure of psychopathology, it is important to review several basic concepts. SYNDROMES, DISEASES, CATEGORIES, AND CONTINUA
Although it is convenient to think of diseases as being discrete entities with discrete identifiable etiologies, many well-defined disorders are extremes of continua in which clinical caseness is statistical in nature. For example, the distribution of diastolic blood pressure in the general population shows no distinct categories or groups even though we know that very high or very low diastolic blood pressures are associated with serious clinical consequences. The current guidelines for saying who is hypertensive or hypotensive are based on statistical criteria that aim to
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minimize both the negative consequences of extremes of blood pressure as well as the potential negative consequences of treatment. The majority of our diagnoses for psychiatric problems, as codified in the Diagnostic and Statistical Manual (DSM-IV) or the International Classification of Disease (ICD-10), are categoric (one does or does not have the condition). Because in general we lack discrete etiologic factors of overwhelming importance for our diagnoses, most psychiatric diagnoses are also syndromatic in nature. That is, our diagnoses are collections of signs and symptoms that occur more frequently in individuals than would be expected based on the prevalences of these signs and symptoms in the general population. This concept of a syndrome is both epidemiologic and statistical. Hence, to make the majority of our diagnoses, we require epidemiologic information on the occurrence of both individual signs and symptoms as well as their co-occurrence within individuals. Of course this is problematic for our field because the estimates of the prevalence of most child or adolescent syndromes, signs, or symptoms in the general population have poor accuracy. In general, we also lack sufficient data to test critically whether disorders are discrete or are extremes of continua. Such problems with epidemiologic accuracy may not be so problematic for rare serious disorders such as autism, but as we argue, even in such uncommon disorders a lack of systematic information from large population samples may result in misconceptions about the underlying nature of such disorders. Researchers in child psychopathology usually lament that they cannot apply the same rigorous definition of disease to syndromes as can be done in other branches of medicine. This should not be misconstrued, however, as being due to fundamental differences in the nature of our disorders but should be looked at as a problem of the difficulty we have in measurement and experimental design. We note that similar problems directly confronted our colleagues in other fields such as infectious disease. For example, the time-tested postulates of Koch with respect to the necessary and sufficient conditions for developing a disease of infectious origin cannot be applied to many of the infectious agents or suspected infectious disorders that are of concern to us today. For many viruses and bacteria thought to be important in different disorders, there are no appropriate laboratory models for passage of the organism or for demonstrating infectivity, nor are there sensitive tests for the detection of the organism in all cases of the disorder. This has led to a relaxation of the clear-cut criteria of 18th-century German medicine to an epidemiologic- and statistical-based definition of disease even when the causative agent is thought to be known. As discussed previously, the concept of discrete diseases or disorders is frequently inappropriate. For many common entities there is no clear-cut distinction between who is affected or unaffected in the general population. The above discussion of blood pressure also can be applied to levels of glucose or cholesterol and associated disorders. Although it is true that particular genetic factors can be associated with "familial" cases of hypercholesterolemia19 or diabetes mellitus, 2• 24 such discrete
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factors account for a small percentage of the variance of serum cholesterol or glucose levels in the general population.
FAMILIALITY AND HERITABILITY
As outlined by Robins and Guze,27 one of the often-used criteria for the validity of a given diagnosis is familial specificity. By this we mean that the prevalence of a given diagnosis among family members is higher than in the general population and is also higher than other unrelated diagnoses. That is, the concordance rate among family members is higher than the prevalence of the disorder in the general population. In its most general form, such family concordance may be among biologic or adoptive relatives. As with the definition of a syndrome or disease, the definition of familiality is epidemiologic and statistical in nature, as one must have an estimate of the prevalence of illness among both the relatives of the proband (the individual who brings the family to attention) and the general population. This may be estimated by several types of family designs (Figs. 1 and 2). Such familiality may be caused by environmental factors such as a common cultural context or common exposure to specific traumatic events, genetic factors, and so forth. Whatever the origin of familiality, the etiologically significant
Figure 1. Four examples of family-based research designs traditionally used for the elucidation of factors contributing to disease etiology. In all figures a solid symbol represents a case, and an open symbol represents a control or unknown phenotype status for an individual. Squares represent men, and circles represent women. A, The traditional and most widely used design is the case-control design, in which no information is considered from family members. B, The traditional case-control design is expanded to include family information on closely related relatives. In each case the individual identifying the family (the proband) is indicated by an arrow. C, In the extended family-control design, more distantly related relatives are studied. This includes siblings and cousins, who experience the same cohort or period effects in environment. 32 In this case, individuals who are related to the proband (arrow) and who have the same disorder (solid squares or circles) should be more similar to the proband than those relatives who are not related. Such an extended family design is widely used in linkage studies that identify genetic loci associated with disease; however, this approach is best suited to rare disorders or simple genetics structures (such as an autosomal-dominant or recessive disease). 0, A newer family design (nontransmitted allele control), in which the proband and parents are identified as usual is shown. The control in this case, however, is those portions of the DNA from the parents not transmitted to the affected offspring (arrow). In this example the parents carry different alleles for a specific locus indicated by AB for the father and CD for the mother. The affected child carries the genotype AC for this locus, whereas the nontransmitted alleles are represented by the dotted line to the hypothetical individual with the genotype BO. Under this scenaro, it is assumed that A or C is associated with the disease, and hence BD is not. To test this, the proportion of transmitted versus nontransmitted alleles or genotypes is determined for a large number of families to see if there is enrichment of one allele or genotype.
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• A
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factor is shared among relatives. An example of an environmental model for familiality is tuberculosis, in which there is a general increase in exposure to the causative agent among relatives living in close proximity, which is related to the amount of contact between individuals rather than their specific biologic relationship. Other environmental models that incorporate biologic relationships, such as child exposure to particular parenting styles, are plausible but in general are difficult to predict a priori. In contrast, most models of risk due to genetic factors follow specific patterns depending on the nature of the gene-syndrome relationship. This may range from a fully expressed autosomal dominant contribution, which results in half of the offspring of an individual being affected, to complex interactions among several genes and/ or environmental elements. Because in general the distribution of genes between
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1.0/0.5
T1
1.0
T2
Figure 2. In the traditional twin study design, twins are determined to be monozygotic (paternal or identical) or dizygotic (fraternal or nonidentical). Given that one twin is affected with the disorder, the concordance rate is calculated for the second twin as a function of being monozygotic or dizygotic. The goal is to determine how twin-twin similarity varies as a function of degree of genetic relatedness. Higher concordance rates for monozygotic compared with dizygotic twins are compatible with genetic factors being important in disease etiology. For twin studies, similarities or differences can be characterized by three factors 17: (1) additive genetic factors are identical for monozygotic twins but only shared 50% of the time (on average) by dizygotic twins; (2) common environment is by definition shared 100% by twins regardless of zygosity; and (3) unique environment is not correlated between the two twins. It should be noted that unique environment also includes any noncorrelated errors in measurement of the phenotype. A = additive genetic; C = common environment; E = unique environment; T1 = twin 1; T2 = twin 2.
parents and children follows simple rules, it is possible to predict the phenotypic outcomes of a variety of genetic models. A common notation and conceptualization of this principle has been proposed by Risch25 in which a ratio, A.R, is defined by the prevalence of the disorder in a given class of relatives of the proband divided by the prevalence of the disorder in the general population. The behavior of A.R among biologic relatives can be specified for different classes of relatives for a given genetic model without knowing any of the specific gene elements involved. It should be noted, however, that estimates of A.R are no better than the estimates of recurrence risk among family members and estimates of prevalence in the general population. This can be particularly problematic when the diagnosis is a quantitative entity such as hypertension versus a categoric entity. Although it is certainly conceivable that a clever researcher could propose a complex environmental model that would mimic the effects of a given set of A.R ratios, it is difficult to propose such models a priori. Hence, a "relative" risk approach to estimating heritability has the compelling logic of the application of simple genetic rules. What underlies all estimates of heritability is the degree to which
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Table 1. DNA SHARING BY RELATIVES Relative Pair
DNA Shared (% IBD)
Correlation for IQ*
Monozygotic twins Dizygotic twins Siblings Adopted away siblings Parent:child Aunt/ uncle:niece I nephew First cousins Spouses Parent:adopted child
100 50 50 50 50 25 12.5 0 0
0.86 0.60 0.47 0.34 0.42 NR 0.15 0.33 0.19
IBO = identical by descent; NR = not reported. *Data from Bouchard TJ, McGue M: Familial studies of intelligence: A review. Science 212:1055-1059, 1981.
parents and offspring share genes or DNA sequences that are identical by descent (passed from parent to child; see Fig. 1 and Table 1). That is, the offspring receives a set of usually exact copies of parental DNA sequences, which are frequently shuffled by recombination and occasionally changed by mutation. For example, monozygotic twins are 100% identical with each other (see Fig. 2; exceptions are notable but rare). In contrast, dizygotic or fraternal twins are 50% identical by descent (IBD) with each parent and on average are 50% IBD with each other. Similarly, grandparent-grandchild pairs are on average 25% IBD and first cousins are on average 12.5% IBD. These differences in percent IBD of DNA sequences for different classes of relatives form the basis of prediction for genetic models. In the absence of specific information about a causative DNA sequence, these estimates apply only to groups of relatives and, hence, are statistical in nature. It should be kept in mind then that definitions of illness and estimates of familiality, whether environmental or genetic in nature, are probabilistic in nature and therefore are not absolute proof of causation. Lacking identification of specific environmental agents or DNA mutations, we must remain humble in our interpretation of findings of familiality and not come to extreme conclusions that are not warranted by the statistical nature of our evidence. ENVIRONMENT, CULTURE, AND MEASUREMENT ERROR
As described, familiality of illness, which for many childhood-onset disorders appears to be strong, may involve genetic or environmental factors or both. Although one might argue whether two individuals ever experience the same environment, environmental effects are usually parceled into those that are thought to be common to a class of individu-
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als and those thought to be unique to a given individual (or uncorrelated among a class of individuals). Common environmental influences may range from nuclear family factors such as parenting style to group factors such as religious or cultural orientation to factors that influence large segments of the population, such as war, famine, disease, or social revolution. Indeed, evolutionary biologists have frequently invoked common environmental factors such as climactic change or widespread famine as being the cause of genetic or cultural bottlenecks by elimination of large segments of the population. On a more microcosmic level, common environmental factors may be peer-group influences or socioeconomic factors. In contrast, unique environmental factors are those experiences that are different for different members of a sibship or a group of family members. They may involve unique insults, such as injury or illness, or may be due to different cultural factors that act as a function of age on a given individual. This latter mechanism, which cannot account for differences among twins (who are the same age), may be important in differences among nontwin siblings. Similarly, sexbased environmental differences, which may affect boys and girls as classes, are unique environmental experiences for opposite sex twin pairs and opposite sex nontwin siblings. Although these examples of distinctions between shared and unique environment are commonly appreciated, it must be emphasized that random errors in measurement between individuals are uncorrelated and will be parceled out as unique environmental experience. Hence, although much has been made about the relatively large estimates of a unique environment compared to a common environment for many behaviors and symptoms of relevance to child psychopathology,22 many studies either have measurement errors of similar magnitude to unique environment estimates or have no stated measurement error estimates at all. The effect of random errors in measurement is to decrease the magnitude of estimates of both genetic and common environmental factors. From this point of view, measured values of the contributions of genetic and common environmental factors should be viewed as minimal estimates. An underlying assumption of most studies of family resemblance (whether investigating genetic or shared family environment effects) is that parents have mated at random with respect to the characteristics under study. It is quite clear that individuals in marriages or other unions that produce offspring have not randomly chosen one another because there are on average marked similarities in age, socioeconomic status, religion, race/ ethnicity, and so forth among mothers and fathers. Whether such so-called "assortative" mating includes biases in reproduction based on psychiatric status is less clear. As reviewed recently by Maes et al,14 a number of studies have found evidence for marital resemblance for both psychiatric disorders and combinations of psychiatric disorders. In an analysis of two large population-based twin samples, Maes et al14 did find a moderate degree of assortative mating both within and across psychiatric disorders. This was on the order of 0% to
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20%. Only a small amount of the observed assortative mating could be explained by correlated variables such as age, education, or religious attendance. Su ch assortative mating would tend to increase estimates of a shared common environment and decreased estimates of genetic factors in twin studies; however, simulations 14 suggest that such effects would be minimal secondary to the modest degree of observed assortative mating.
GENETIC BASIS OF ANIMAL BEHAVIOR
As outlined by Plomin, 22 applied behavioral genetics has existed for thousands of years in the domestication of animals for both morphologic and behavioral characteristics. This can be easily observed by a visit to any dog breeder or humane society facility, where the animal handlers can reliably predict the adult size, the expected aggressivity, and the degree of intelligence of individual pure-bred and mixed-breed puppies. Breeds such as pitbulls are known for aggressive/territorial behavior, whereas breeds such as Australian shepherds are known for intelligence, trainability, and herding instincts. Similarly, a variety of behaviorally distinct laboratory animal strains have been inbred for multiple generations by selecting for a variety of behavioral characteristics ranging from the ability to perform maze tests to the degree of alcohol or nicotine ingestion. The results of such animal-breeding experiments (which mimic the evolutionary selection of traits in nature) have several implications for studies of child and adolescent psychopathology. First, for both simple and complex behaviors, it is easy to demonstrate the existence of genetic contributions to behavior. Second, the overall heritability estimates for behaviors selected for in this fashion are usually less than 50%. That is, most of the familiality of a specific behavior is not genetic in origin but is due to environmental factors. Finally, for the majority of selected behavioral traits, the genetic structure is complex and appears to involve many genes. Although many strains that have been developed by planned mutagenesis or by capitalizing on spontaneous mutations have extreme single-gene phenotypes reminiscent of Mendelian disorders, the normal range of behavioral variability found in these inbred strains cannot be accounted for by the effects of a few genes. To the extent we determine that child and adolescent psychopathologic disorders are best viewed as extremes of normal variation in behavior, then by analogy with animal-breeding experiments we can expect that these behaviors will involve the influence of a variety of genes and that the magnitude of genetic effects will in general not exceed 50% of the explainable variance. This of course implies there may be important environmental intervention points in modifying or preventing the expression of deleterious gene effects without requiring direct gene therapy interventions. The classic example of this is phenylketonuria, an autosomal-recessive disorder, in which elimination of phenylalanine from the
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diet from early in life minimizes the developmental effects of mutations in the phenylalanine hydroxylase gene. ENVIRONMENTAL BASIS OF ANIMAL BEHAVIOR
A major theme of developmental theory in psychology has been that early experiences disproportionally influence human adult behavior. This notion has been difficult to document at the human level secondary to ethical considerations of experimental design; however, as reviewed by Suomi,30 there is compelling evidence for such long-lasting influences of early environmental experience in animal studies. In particular, studies of rhesus monkeys have demonstrated the importance of early social relationships with caregivers for behavioral and physiologic characteristics throughout life. For example, different rearing circumstances (both with respect to the type of caregiver and the size of the social group) affect the expected increase in plasma cortisol in response to the stress of short-term isolation. 28 Individual behavioral differences in rhesus monkeys, which may be due to either genetic differences or early rearing experiences, may also be overwhelmed by extreme environmental stressors later in life. 10 For these behavioral and physiologic effects, however, the true situation is likely to include both important environmental and genetic components. For example, a variety of human and primate studies have demonstrated an inverse relationship between certain types of aggressive or self-injurious behavior and cerebral spinal fluid serotonin metabolite levels. Recent primate work has also demonstrated important species and inter-individual differences in serotonin metabolite levels, which correlate positively with social position and inversely with aggression.4' 34 These metabolite levels are not static and can change with environmental manipulations such as alterations in the social hierarchy of a troop. In contrast, Clarke et al5 have presented evidence that basal serotonin and other monoamine metabolite levels in the cerebral spinal fluid of rhesus monkeys are under genetic control. As suggested by Clarke et al,5 studies incorporating both genetic and environment factors are likely to be more productive in understanding normal behaviors and vulnerability to psychopathology. GENETICS AND NORMAL HUMAN BEHAVIOR
Before discussing the importance of and mechanisms of contribution of genetic factors to child and adolescent psychopathology, it is important to remember that a variety of normal human behaviors and abilities appear to be under significant genetic control. The example of circadian rhythm was discussed previously. Similarly, a variety of troubling but nonpathologic childhood behaviors such as enuresis, sleep walking, nail biting, or thumb sucking have significant heritabilities in
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the range of 0.3 to 1.0. 16 Similarly, a variety of twin and adoption studies have estimated the genetic contributions to personality/temperament features to be on the order of 30% to 50%.20, 29 Perhaps the best-studied "normal" behavior trait in humans is general cognitive ability (so-called IQ). In a massive compilation of more than 100 family studies of intelligence, Bouchard and McGue 3 found a marked correlation of IQ scores with the percent DNA shared identical by descent for various classes of relatives (see Table 1). For example, the overall correlation from monozygotic twins was 0.86, whereas the overall correlation of dizygotic twins was 0.60, which is compatible with a broad heritability of about 50%. At the same time, however, there was evidence for assortative mating because the correlation for biologically unrelated spouses was about 33%. Other environmental effects are also likely because although the correlation among nontwin siblings was 0.47, this correlation dropped to 0.34 for adopted-away siblings. This is in keeping with newer studies estimating the heritability of IQ, which suggests that overall the heritability for general cognitive ability is about 50%. The estimated errors were thought to be on the order of 20% across these studies, suggesting that the true heritability of our general cognitive ability is somewhere between 30% and 70%. In particular, Plomin has investigated cognitive ability as a function of age.23 These studies have been illuminating in that from infancy to early school years estimates of the heritability of IQ increase and appear to be highly correlated with genetic effects of IQ in adulthood. Recently, this has been extended to elderly twin pairs demonstrating persistent genetic effects on IQ even though the magnitude of their unique environmental experience has presumably increased over the course of their lifetime. This brief summary of both animal breeding and human family studies regarding normal behavioral traits suggests that many of the symptom domains that are found to be involved in psychopathologic states are under marked genetic control in the general population and that the underlying basis of this control is the action of multiple genes for each trait. This is compatible with the recognized continuous distributions of trait attributes in the normal population and, as will be discussed next, has implications for the nature of psychopathologic disorders. WHAT IS THE STRUCTURE OF CHILD AND ADOLESCENT DISORDERS?
As outlined herein, to investigate the etiology of psychopathologic disorders, one needs to take an evolutionary and epidemiologic perspective. Unfortunately, few of our disorders have sufficient epidemiologic data on the presence of individual or groups of psychiatric symptoms to allow critical tests of the structure of disorders. Similarly, we lack sufficient knowledge of the environmental context of symptoms over evolutionary time periods to gauge whether today's problem behaviors
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were advantageous or neutral in the past.31 In particular, we lack sufficient data to determine whether symptom domains represent discrete disorders, discrete continua, or some mixture of categoric and continuum entities. Similarly, whether the observed comorbidities (that is, the presence of two or more diagnostic entities in the same individual) reflect the familial aggregation of different illnesses via mechanisms such as assortative mating or reflect distinct genetic subtypes of disorders is also unclear. These problems and their subsequent impact on the diagnosis, treatment, or investigation of our clinical entities are highlighted by the examples of autism and attention-deficit/hyperactivity disorder (ADHD). These two examples are chosen secondary to their reported differences in prevalence and morbidity. Autism is thought to be a rare and severe early-onset disorder characterized by (1) qualitative impairments in social interactions, (2) communication deficits, and (3) restricted, repetitive, and stereotypical patterns of behavior, interest, and activities (DSM-IV). Other related pervasive developmental disorders share deficits in social interactions but have variable presence of the other features of autism. A variety of twin and family studies of categorically defined illness have demonstrated that autism is largely genetically determined.1 Interestingly, twin and family studies have also shown that the abnormal social behaviors characteristic of autism significantly aggregate in family members of autistic probands.12• 21• 36 Strikingly, no population-based studies have been reported regarding the prevalence of individual autism symptoms or groups of symptoms in the general population. In the course of developing a screening instrument for the identification of pervasive developmental disorder cases for use by parents and schoolteachers, we unexpectedly found a continuous distribution of endorsement of social interaction symptoms in a random sample of students.6 A significant fraction of these students received symptom scores overlapping with a clinic-based group of autistic and pervasive developmental disorder patients. That is, the clinic cases were at the high end of the distribution of scores in this instrument, but there was no clear dividing line between the scores of school children and clinical cases. A variety of clustering procedures was compatible, with problems of social interaction being a continuous variable in this population. This questionnaire was then completed by a parent for more than 200 male:male twin pairs aged 9 to 14 years as identified through birth records of the state of Missouri. Once again, in this population-based sample of twins, social interaction problem scores appear continuously distributed. Monozygotic twin pairs had significantly higher correlations for scores than dizygotic twin pairs, which is consistent with the involvement of genes for this characteristic. More formal twin analysis estimated the heritability of scale scores to be 75% with no evidence for common environment contributions to family resemblance. 6• The results of these two studies taken together with previous twin and family studies of autism suggest that at least one of the core features of autism (problems
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with social interactions) may be continuously distributed in the population and that families of autistic individuals lie at one extreme end of this continuum. Given both the reported high heritabilities of autism and our estimates of the heritability of social problems in the general population it is possible that autism is not a rare categoric disorder as described in DSM-IV but is the extreme end of a population distribution with no clear division between affected and unaffected status. This concept is compatible with the results of recent studies trying to identify genes for autism that suggest that a large number of genetic loci are likely to be involved in categorically defined cases of autism. 26 In contrast to autism, ADHD is thought to be common and although associated with impairments in school, peer, or home functioning is clearly not as incapacitating as autism (DSM-IV). A variety of twin studies (whether of categoric diagnoses, symptom counts, or scale measures) are compatible with autism having a heritability in the range of 0.6 to 0.9.7 Under DSM-IV criteria ADHD occurs in three mutually exclusive subtypes referred to as inattentive, hyperactive/impulsive, and combined. Little data have been reported on the relative heritabilities of these DSM-IV subtypes, but a number of studies have attempted to look independently at the heritability of inattentive and hyperactive/ impulsive symptoms. 33 Based on such analyses, several investigators have suggested that ADHD is best viewed as a continuum of problems with inattentive and hyperactive/impulsive symptoms. 8, 13 We have attempted to test formally whether ADHD is best conceived of as a categoric or continuum disorder by the application of parametric and nonparametric clustering procedures to DSM-IV ADHD symptom data reported by parents on their children (Todd RD, Neuman RJ, Reich W, et al: submitted for publication). 8 ' 18, 18• Our initial results based on a sample of approximately 1500 female twin pairs identified from birth records of the state of Missouri were interpreted as supporting a continuum position, 8 in which there were separate continua for inattention problems, hyperactive/impulsive problems, and combined subtype problems. Similar results were found for both boys and girls in a sample of families identified through alcoholic probands. 18 Further analyses on an enlarged sample of more than 2000 female twin pairs, however, support a different model. 18• In a continuum model, twins in the same twin pair would be expected to lie along the same portion of the continuum but not necessarily at the same point. In contrast, if the apparent continuum is represented by multiple independent types of ADHD, then twin pair members would be expected to have the same type of ADHD. Analysis of within and between twin pair phenotypes using a clustering procedure referred to as latent class analysis 15 is most compatible, with multiple genetically independent forms of ADHD in this general population sample of female twins (Todd RD, Neuman RJ, Reich W, et al: submitted for publication).
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In both of these examples, careful attention to the collection and interpretation of population-based data results in models that challenge current views of the structure of these two psychopathologic conditions. For autism, it is suggested that caseness represents the end of a distribution of deviance in the general population. In contrast, for ADHD there may be multiple genetically independent forms of ADHD in the general population, which only partially overlap with DSM-IV conceptualizations of illness. Both these findings have implications for study designs aimed at identifying genetic factors involved in these illnesses and for clinical practice. First, current estimates of the multi-locus etiology of autism suggest that sufficient multiplex autism families may not exist to allow the definition of the responsible DNA elements. An alternative strategy for the identification of these genetic elements, however, would be to take sibling pairs from the general population who differ on quantitative measures of social interaction problems (a discordant quantitative trait locus [QTL] design). Specific associations found in such general population studies could then be secondarily tested in singleton and multiplex autism families. Similarly for ADHD, linkage analysis of extended pedigrees may be inappropriate. First, if ADHD is in fact composed of multiple genetically independent forms of ADHD, the use of extended families is likely to introduce genetic heterogeneity within single pedigrees. This greatly increases the difficulty of identifying susceptibility loci. Similarly, the use of DSM-IV ADHD subtypes for analysis would likely decrease the power of studies due to the mixing of different independently heritable subtypes. In the case of ADHD it may be more cost effective to focus on nuclear families with particular heritable subtypes identified through population samples as described earlier. With respect to the clinical problems of who and when to treat, the results of the earlier discussions suggest these will be different for autism and ADHD. The presence of multiple genetically independent forms of ADHD may suggest specific treatments for individual subtypes. Hence, in the future it may be possible to direct pharmacologic or behavioral treatments for ADHD based on either clinical or genotype information. For autism, if the true underlying problems represent a continuum, then the decision to call an individual affected or not must include riskbenefit analyses of individual treatments because the conceptualization of caseness is arbitrary. CONCLUSIONS
As outlined in this article, studying the etiology of child and adolescent psychopathology may require establishing an evolutionary and epidemiologic context. Although increases in our understanding of past environmental pressures and history over evolutionary time periods may be limited by a fragmented historic record, we can make advancements in understanding the epidemiology and significance of individual symptoms and groups of symptoms to best determine the underlying
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structure of psychopathology. By placing nosologic or etiologic studies in a family/ genetic design, the relative magnitude of both environmental and genetic effects (and possible interactions among these) can be determined while controlling in a natural way for a variety of potential confounding variables. In particular, the application of such techniques may help determine the true underlying structures of psychiatric disorders and enhance the ability to identify mutations or allelic DNA sequence differences contributing to psychopathology. It is hoped that defining DNA variations contributing to psychopathology will enhance the power of treatment studies whether they are of behavioral, pharmacologic, or other substance. ACKNOWLEDGMENTS The author thanks his colleagues and the families who have participated in the studies described in this article and John Constantino, MD, for commenting on an earlier draft of the manuscript.
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Address reprint requests to Richard D. Todd, PhD, MD Department of Psychiatry, Box 8134 Washington University School of Medicine 660 South Euclid Avenue St. Louis, MO 63110