lBAB I

PENDAHULUAN
PERKEMBANGAN ILMU GENETIK DALAM PSIKIATRI As a result of advances in neural science in the last several years, both psychiatry and neural science are in a new and better position for a rapprochement, a rapprochement that would allow the insights of the psychoanalytic perspective to inform the search for a deeper understanding of the biological basis of behavior. As a first step toward such a rapprochement, I here outline an intellectual framework designed to align current psychiatric thinking and the training of future practitioners with modern biology.This framework can be summarized in five principles that constitute, in simplified form, the current thinking of biologists about the relationship of mind to brain. Principle 1. All mental processes, even the most complex psychological processes, derive from operations of the brain. The central tenet of this view is that what we commonly call mind is a range of functions carried out by the brain. The actions of the brain underlie not only relatively simple motor behaviors, such as walking and eating, but all of the complex cognitive actions, conscious and unconscious, that we associate with specifically human behavior, such as thinking, speaking, and creating works of literature, music, and art. As a corollary, behavioral disorders that characterize psychiatric illness are disturbances of brain function, even in those cases where the causes of the disturbances are clearly environmental in origin. Principle 2. Genes and their protein products are important determinants of the pattern of interconnections between neurons in the brain and the details of their functioning. Genes, and specifically combinations of genes, therefore exert a significant control over behavior. As a corollary, one component contributing to the development of major mental illnesses is genetic. Principle 3. Altered genes do not, by themselves, explain all of the variance of a given major mental illness. Social or developmental factors also contribute very importantly. Just as combinations of genes contribute to behavior, including social behavior, so can behavior and social factors exert actions on the brain by feeding back upon it to modify the expression of genes and thus the function of nerve cells. Learning, including learning that results in dysfunctional behavior, produces alterations in gene expression. Thus all of nurture is ultimately expressed as nature. Principle 4. Alterations in gene expression induced by learning give rise to changes in patterns of neuronal connections. These changes not only contribute to the biological basis of individuality but presumably are responsible for initiating and maintaining abnormalities of behavior that are induced by social contingencies. Principle 5. Insofar as psychotherapy or counseling is effective and produces long-term changes in behavior, it presumably does so through learning, by producing changes in gene expression that alter the strength of synaptic connections and structural changes that alter the anatomical pattern of interconnections between nerve cells of the brain. As the resolution of brain imaging increases, it should eventually permit quantitative evaluation of the outcome of psychotherapy.

The key concept of importance here is that genes have dual functions. First, genes serve as stable templates that can replicate reliably. This template function is exercised by each gene, in each cell of the body, including the gametes. It is this function that provides succeeding generations with copies of each gene. The fidelity of the template replication is high. Moreover, the template is not regulated by social experience of any sort. It can only be altered by mutations, and these are rare and often random. This function of the gene, its template (transmission) function, is indeed beyond our individual or social control. Second, genes determine the phenotype; they determine the structure, function, and other biological characteristics of the cell in which they are expressed. This second function of the gene is referred to as its transcriptional function. Although almost every cell of the body has all of the genes that are present in every other cell, in any given cell type (be it a liver cell or a brain cell) only a fraction of genes, perhaps 10%20%, are expressed (transcribed). All of the other genes are effectively repressed. A liver cell is a liver cell and a brain cell is a brain cell because each of these cell types expresses only a particular subset of the total population of genes. When a gene is expressed in a cell, it directs the phenotype of that cell: the manufacture of specific proteins that specify the character of that cell. Whereas the template function, the sequence of a geneand the ability of the organism to replicate that sequence is not affected by environmental experience, the transcriptional function of a genethe ability of a given gene to direct the manufacture of specific proteins in any given cellis, in fact, highly regulated, and this regulation is responsive to environmental factors. A gene has two regions (figure 1). A coding region encodes mRNA, which in turn encodes a specific protein. A regulatory region usually lies upstream of the coding region and consists of two DNA elements. The promoter element is a site where an enzyme, called RNA polymerase, will begin to read and transcribe the DNA coding region into mRNA. The enhancer element recognizes protein signals that determine in which cells, and when, the coding region will be transcribed by the polymerase. Thus, a small number of proteins, or transcriptional regulators, that bind to different segments of the enhancer element determine how often RNA polymerase binds to the promoter element and transcribes the gene. Internal and external stimulisteps in the development of the brain, hormones, stress, learning, and social interactionalter the binding of the transcriptional regulators to the enhancer element, and in this way different combinations of transcriptional regulators are recruited. This aspect of gene regulation is sometimes referred to as epigenetic regulation. Stated simply, the regulation of gene expression by social factors makes all bodily functions, including all functions of the brain, susceptible to social influences. These social influences will be biologically incorporated in the altered expressions of specific genes in specific nerve cells of specific regions of the brain. These socially influenced alterations are transmitted culturally. They are not incorporated in the sperm and egg and therefore are not transmitted genetically. In humans the modifiability of gene expression through learning (in a nontransmissible way) is particularly effective and has led to a new kind of evolution: cultural evolution. The capability of learning is so highly developed in humans that humankind changes much more by cultural evolution than by biological evolution. Measurements of skulls found in the fossil record suggest that the size of the human brain has not changed since Homo sapiens first appeared approximately 50,000 years ago; yet clearly, human culture has evolved dramatically in that same time.

Genes Contribute Importantly to Mental Function and Can Contribute to Mental Illness Let us consider the contribution of the template functions of DNAthe heritable aspects of gene action. Here we first need to ask, How do genes contribute to behavior? Clearly, genes do not code for behavior in a direct way. A single gene encodes a single protein; it cannot by itself encode for a single behavior. Behavior is generated by neural circuits that involve many cells, each of which expresses specific genes that direct the production of specific proteins. The genes expressed in the brain encode proteins that are important in one or another step of the development, maintenance, and regulation of the neural circuits that underlie behavior. A wide variety of proteinsstructural, regulatory, and catalyticare required for the differentiation of a single nerve cell, and many cells and many more genes are required for the development and function of a neural circuit. To account for what we now appreciate as variations in the template functions of a gene, Darwin and his followers first postulated that variations in human behavior may, in part, be due to natural selection. If this is so, some element of the behavioral variation in any population will necessarily have a genetic basis. Some portion of this variation in turn should show up as clearly heritable differences. Control studies of heritable factors in human behavior have proven difficult to devise, because it is not possible or desirable to control an individuals environment for experimental purposes except in some very limited situations. Thus, behavioral studies of identical twins provide important information not otherwise available. Identical twins share an identical genome and are therefore as alike genetically as is possible for two individuals. Similarities between identical twins who have been separated early in life and raised in different households, as occasionally happens, will therefore be more attributable to genes than to environment. Identical twins, compared with a group of individuals matched in age, sex, and socioeconomic status, share a remarkable number of behavioral traits. These include tastes, religious preferences, and vocational interests that are commonly considered to be socially determined and distinctive features of an individual. These findings argue that human behavior has a significant hereditary component. But the similarity is far from perfect. Twins can and do vary a great deal. Thus, twin studies also emphasize the importance of environmental influences; they indicate quite clearly that environmental factors are very important (16). A similar situation applies to disturbances of behavior and to mental illness. The first direct evidence that genes are important in the development of schizophrenia was provided in the 1930s by Franz Kallmann (18). Kallmann was impressed with the fact that the incidence of schizophrenia throughout the world is uniformly about 1%, even though the social and environmental factors vary dramatically. Nevertheless, he found that the incidence of schizophrenia among parents, children, and siblings of patients with the disease is 15%, strong evidence that the disease runs in families. However, a genetic basis for schizophrenia cannot simply be inferred from the increased incidence in families. Not all conditions that run in families are necessarily genetic: wealth and poverty, habits, and values also run in families, and in earlier times even nutritional deficiencies such as pellagra ran in families.

FIGURE 1. Genetic Transcriptional Control (adapted from Schwartz and Kandel [17])a

aA:

The typical eukaryotic gene has two regions. The coding region is transcribed by RNA polymerase II into an mRNA and is then translated into a specific protein. The regulatory region, consisting of enhancer elements and a promoter element, which contains the TATA box (T=thymidine, A=adenine), regulates the initiation of transcription of the structural gene. Transcriptional regulatory proteins bind both the promoter and the enhancer regions. B(1): A set of proteins (such as TATA box factors IIA, IIB, IID, and others) binds to the TATA box, to the promoter, and to the distal enhancer regions. B(2): Proteins that bind to the enhancer region cause looping of the DNA, thereby allowing the regulatory proteins that bind to distal enhancers to contact the polymerase.

A New View of the Relationship Between Inherited and Acquired Mental Illnesses In the few instances where it has been possible to examine rigorously the persistent changes in mental functions, these functions have been shown to involve alterations in gene expression. Thus, in studying the specific changes that underlie persistent mental states, normal as well as disturbed, we should also look for altered gene expression. As we have seen, there is now substantial evidence that the susceptibility to major psychotic illnesses (schizophrenia and manic-depressive disorders) is heritable. These illnesses in part reflect alterations in the template function of the genein the nucleotide sequence of a number of different genesleading to abnormal mRNAs and abnormal proteins. It is therefore tempting to think that insofar as psychiatric illnesses such as posttraumatic stress syndrome are acquired by experience, they are likely to involve alterations in the transcriptional function of the genein the regulation of gene expression. Nonetheless, some individuals may be much more susceptible to this syndrome because of the combination of genes they have inherited. Development, stress, and social experience are all factors that can alter gene expression by modifying the binding of transcriptional regulators to each other and to the regulatory regions of genes. It is likely that at least some neurotic illnesses (or components of them) result from reversible defects in gene regulation, which may be due to altered binding of specific proteins to certain upstream regions that control the expression of certain genes (figure 2).

Maintenance of Learned Alterations in Gene Expression by Structural Alterations in Neural Circuits of the Brain How does altered gene expression lead to the stable alterations of a mental process? Animal studies of alterations in gene expression induced by learning indicate that one major consequence of such alterations in gene activation is the growth of synaptic connections. This growth was first delineated by studies in simple invertebrate animals such as the snail Aplysia (25). Animals subjected to controlled learning that gave rise to long-term memory had twice as many presynaptic terminals as untrained animals. Some forms of learning, such as long-term habituation, produce the opposite changes; they lead to a regression and pruning of synaptic connections. These morphological changes seem to be a signature of the long-term memory process. They do not occur with short-term memory. In mammals, and especially in humans, each functional component of the nervous system is represented by hundreds of thousands of nerve cells. In such complex systems a specific instance of learning is likely to lead to alterations In a large number of nerve cells insofar as the interconnections of the various sensory and motor systems involved in the learning are changed. Indeed, studies have shown that such vast changes do occur. The most detailed evidence has come from studies of the somatic sensory system. The primary somatic sensory cortex contains four separate maps of the surface of the body in four areas in the postcentral gyrus (Brodmanns areas 1, 2, 3a, and 3b). These cortical maps differ among individuals in a manner that reflects their use. Moreover, the cortical maps for somatic sensations are dynamic, not static, even in mature animals (26). The distribution of these functional connections can expand and retract, depending on the particular uses or activities of the peripheral sensory pathways. Since each of us is brought up in a somewhat different environment, exposed to different combinations of stimuli, and we develop motor skills in different ways, each brain is modified in unique ways. This distinctive modification of brain architecture, along with a unique genetic makeup, constitutes the biological basis for individuality. Two studies provide evidence for this view (26). One study found that the somatosensory maps vary considerably among normal animals. However, this study did not separate the effects of different experiences from the consequences of different genetic endowment. Another study was conducted to see whether activity is important in determining the topographic organization of the somatosensory cortex. Adult monkeys were encouraged to use three middle fingers at the expense of two other fingers of the hand to obtain food. After several thousand trials, the area of cortex devoted to the three fingers was greatly expanded at the expense of the area normally devoted to the other fingers (figure 3). Practice alone, therefore, may not only strengthen the effectiveness of existing patterns of connections, but also change cortical connections to accommodate new patterns of actions.

FIGURE 2. There Is a Genetic Component to Both Inherited and Acquired Psychiatric Illness (adapted from Kandel [24])a

aGenetic

and acquired illnesses both have a genetic component. Genetic illnesses (e.g., schizophrenia) are expressions of altered genes, whereas illnesses acquired as learned behavior (neuroses) involve the modulation of gene expression by environmental stimuli, leading to the transcription of a previously inactive gene. The gene is illustrated as having two segments. A coding region is transcribed into an mRNA by an RNA polymerase. The mRNA in turn is translated into a specific protein. A regulatory segment consists of an enhancer region and a promoter region. In this example the RNA polymerase can transcribe the gene when the regulatory protein binds to the enhancer region. For gene activation to occur, the regulatory protein must first be phosphorylated. A(1): Under normal conditions the phosphorylated regulatory protein binds to the enhancer region, thereby activating the transcription of the gene, leading to the production of the protein (P=phosphorus, A=adenine, C=cytosine, G=guanine, T=thymidine). A(2): A mutant form of the coding region of the structural gene, in which a T has been substituted for a C, leads to transcription of an altered mRNA. This in turn produces an abnormal protein, giving rise to the disease state. This alteration in gene structure becomes established in the germ line and is heritable. B(1): If the regulatory protein for a normal gene is not phosphorylated, it cannot bind to the enhancer site, and thus gene transcription cannot be initiated. B(2): In this case a specific experience leads to the activation of serotonin (5-HT) and cAMP, which activate the cAMP-dependent protein kinase. The catalytic unit phosphorylates the regulatory protein, which then can bind to the enhancer segment and thus initiate gene transcription. By this means an abnormal learning experience could lead to the expression of a protein that gives rise to symptoms of a neurotic disorder. ERIC R. KANDEL

Am J Psychiatry 155:4, April 1998

In recent years, mental health professionals have become increasingly aware of the importance of genetic factors in the etiology (causes) of mental disorders. Since the Human Genome Project began its mapping of the entire sequence of human DNA in 1990, the implications of its findings for psychiatric diagnosis and treatment have accumulated rapidly. A new subspecialty known as biological psychiatry (also called physiological psychology or psychiatric genetics) has emerged from the discoveries of the last two decades. Biological psychiatry got its start in the late 1980s, when several research groups identified genes associated with manic depression and schizophrenia respectively. These studies ran into difficulties fairly quickly, however, because of the complexity of the relationship between genetic factors and mental illness.

The ongoing search for genes related to psychiatric symptoms and disorders is complicated by several factors:

Psychiatric diagnosis relies on a doctor's human judgment and evaluation of a patient's behavior or appearance to a greater degree than diagnosis in other fields of medicine. For example, there is no blood or urine test for schizophrenia or a personality disorder. Diagnostic questionnaires for mental disorders are helpful in trimming the list of possible diagnoses but do not have the same degree of precision or objectivity as laboratory findings. Mental disorders almost always involve more than one gene. Studies have shown that one mental disorder can be caused by different genes on different chromosomes in different populations. For example, one study in the late 1980s found two genes on two different chromosomes among two populations that caused manic depression. Studies of schizophrenia done in the late 1980s and early 1990s revealed the same finding different genes on different chromosomes produced schizophrenia in different populations. It now appears that specific mental disorders are related to different sets of genes that vary across family and ethnic groups. Genes associated with mental disorders do not always show the same degree of penetrance, which is defined as the frequency with which a gene produces its effects in a specific group of people. Penetrance is expressed as a percentage. For example, a gene for manic depression may have 20% penetrance, which means that 20% of the members of the family being studied are at risk of developing the disorder. Genetic factors in mental disorders interact with a person's family and cultural environment. A person who has a gene associated with susceptibility to alcohol abuse, for example, may not develop the disorder if he or she grows up in a family that teaches effective ways to cope with stress and responsible attitudes toward drinking.

There are several terms in biological psychiatry that are important to understand:

Genotype: A person's genotype is the sum total of the genetic material transmitted from his or her parents. Phenotype: A person's phenotype is the observable signs, symptoms, and other aspects of his or her appearance. The term is also used sometimes to refer to a person's outward appearance and behavior as these result from the interaction between the person's genotype and his or her environment. Behavioral phenotype: The concept of a behavioral phenotype is used most often with reference to patterns of behavior found in certain developmental disorders of childhood, such as Down syndrome or Prader-Willi syndrome. Behavioral phenotype refers to the greater likelihood that people with a specific genetic syndrome will have certain behavioral or developmental characteristics compared to people who do not have the syndrome; it does not mean that every person diagnosed with a given genetic syndrome will invariably develop these characteristics.

There are few reviews of chromosomal abnor malities and psychiatric disorders in the literature.Chromosomal abnormalities may involve either the sex chromosomes (X and Y) or the autosomes(chromosomes 122).Propping (1983) tabulatedthree chromosomal abnormalities associated with possible schizophrenia-like psychoses: XXY, XXX,and 18q- or ring 18. More recently, in the context of their own cytogenetic survey of 46 men with schizophrenia, DeLisi & Lovett (1990) summarized 15 X chromosome studies and four reports of autosomal abnormalities associated with psychoses. Crow (1988) has also examined sex chromosomes and psychotic disorders, an important area with numerous reports dating back to 1962, deserving its own critical review. The focus in the current paper, however, is restricted to autosomal abnormality associations, which have been less discussed than the sex chromo somal anomalies. The present review updates and extends the references catalogued in the Propping (1983) and DeLisi & Lovett (1990) articles, and critically reviews the evidence for reported associations of autosomal abnormalities and psychiatric illness. The relevance of these associations for genetic linkage studies was estimated with standardized criteria for specificity, diagnosis, family history, and overall weight of evidence. The results of this critical review suggest strategies for future studies to detect new chromosomal aberrations associated with major psychotic disorders that may be relevant to isolating a gene for schizophrenia.

Implicationsfor psychiatry

The new DNA technology holds much promise for psychiatry, among other medical disciplines. At the present, the first task should be the genetic characterisation of psychiatric illness. Attention should focus on those disorders which have a strong familial and probably genetic com ponent; affect tive illness and schizophrenia are the most likely candidates, although other conditions with evidence of familiality, such as anxiety and panic disorders, may also be considered. Three strategies can be employed: 1. linkage studies with RFLPs; 2. Cloning of candidate genes; 3. study of gene expression in the brain by analysis of mRNA. Linkage studies with RFLPs The linkage strategy was oulined earlier, but when psychiatric disorders are considered, several important methodological issues must be considered.

(a)Nosology For the purpose of genetic analysis, it would be advantageous to study homogeneous populations. However, with changing diagnostic practices, defming a phenotype for genetic studies may not be a straight forward task, as the question of who is ill and who is well depends on how broaod or_narrow our criteria are. The current emphasis on the structured, criterion-based approaches to psychiatric nosology -e.g. DSMIII(American Psychiatric Association, 1980), the Research Diagnostic Criteria (RDC; Spitzer eta!, 1978),and the Present State Examination (PSE; Wing et a!, 1974) is_certain to improve reliability and consensus among

clinicians, but does not address the question of external validity or the likely clinical heterogeneity within a given diagnosis. Additional data such as differential familial loading, treatment response, and biochemical measures, may aid in dissecting diagnostic categories into more homogeneous subtypes. The current practice of subtyping affective illness into bipolar and unipolar disorders (Rainer, 1985), or schizophrenia to paranoid vs non-paranoid, narrow' vs broad' subtypes,and core schizophrenia vs spectrum disorders (Baron et a!, l985a,b) illustrates this approach. Recombinant DNA methods may aid in refining psychiatric nosology by identifying the genetic defects that are specific to some clinical syndromes and not to others, e.g. in the case of schizophrenia pedigrees (Baron, 1986b). (b) Selection of probes Since it is difficult, if not impossible, to predict where on the human genome the gene for a particular psychiatric disorder resides, it is equally hard to select suitable probes. However, clues that can be used as departure points are available. Firstly, since previous studies of affective illness and schizophrenia have not shown consistent evidence of linkage with conventional autosomal-marker loci (Nurnberger & Gershon, 1982; Baron, 1986b), it can be surmised that a large portion of the human genome (accounting for approximately 20% of the genomic map) can be excluded from future consideration, although this still leaves us with 80% of the genetic code. In the Huntington's disease study (Gusella et al, 1983), linkage was found with a RFLP from a genomic region that could not be excluded as containing the putative disease locus by studies with conventional markers. Also (as reviewed by Baron et al, 1981, 1987; Risch & Baron, 1982), linkage studies with the X-chromosome markers for colour blindness and glucose-6-phosphate dehydrogenase (G6PD) deficiency have raised the possibility that a subset of bipolar affective illness is transmitted in an X-linked fashion. Studies with known RFLPs in that region the distal end of the long arm of the X-chromosome may shed light on this issue. Using the procedure described above (see Gene expression), proteins suspected of being involved in the aetiology of the disorder under study can be used for generating suitable probes; these probes, in turn, can be used in linkage studies (see also, below, Cloning of candidate genes). (c) Mode of inheritance and aetiologicalheterogeneity The DNA strategies described here are predicated on the assumption that some forms of psychiatric disorders are characterised by single-gene trans mission. As reviewed (Rainer, 1985; Baron, 1986a), segregation analysis and related techniques have not resolved the mode of inheritance of psychiatric disorders. However, this finding may be partly attributable to aetiological heterogeneity, and should not preclude the role of major genes in subsets of psychiatric illness; psychiatric disorders are likely to be heterogeneous, with different genetic and non genetic mechanisms underlying different subsets of pedigrees. For any given disorder there may be several different major genes, a polygenic type, and environmental causes. As noted earlier, this problem is further complicated by reduced penetrance and variable expressivity of the genotype. These factors may affect the linkage strategy in two ways. Firstly, as discussed above (see Linkage analysis: statistical preliminaries), the led score linkage approach requires specification of mode of inheritance (single gene transmission) and genetic

parameters; hence, since the mode of inheritance of psychiatric disorders is unknown, it would be necessary to make certain assumptions about the underlying genetic mechanism. While these assumptions may result in inaccurate estimates of the genetic parameters, they are not likely to lead to the acceptance of the linkage hypothesis when in fact it is false (i.e. a type II error); in fact, the assumption of reduced penetrance, for example, may bias against the finding of linkage when linkage is actually present (type I error). The affected sib-pair method circumvents some of these problems since it does not require knowledge of the mode of inheritance and the associated parameters; also, since unaffected siblings are excluded in this analysis, the question of penetrance does not arise. Secondly, the extent of heterogeneity in the disorders of interest is unknown. It is assumed that the number of different aetiologies is not too large for a linkage study to be feasible; it is assumed that if major genes are segregating in the disorder of interest, the cases accounted for by each of these genes are fairly common. The use of multiple-case pedigrees (pedigrees loaded with affected members) may also tend to obviate problems of heterogeneity. Despite these potential limitations, the genetic marker strategy is considered a promising method for unravelling genetic heterogeneity e.g_. linkage to two different markers in different pedigrees may point to two genetic types of the disorder. This approach has been successful in other medical conditions with complex mode of transmission and aetiological heterogeneity, such as retinitis pigmen tosa, mental retardation, and diabetes mellitus ,
(Bhattacharya et al, 1984;Camerino eta!, 1983; Rich et al, 1984; Barker et a!, 1984).

Genetic causality in mental disorders

As of 2002, genes appear to influence the development of mental disorders in three major ways: they may govern the organic causes of such disorders as Alzheimer's disease and schizophrenia; they may be responsible for abnormalities in a person's development before or after birth; and they may influence a person's susceptibility to anxiety, depression, personality disorders , and substance abuse disorders. One technological development that has contributed to the major advances in biological psychiatry in the last twenty years is high-speed computing. Faster computers have enabled researchers to go beyond rough estimates of the heritability of various disorders to accurate quantification of genetic effects. In some cases the data have led to significant reappraisals of the causes of specific disorders. As recently as the 1960s and 1970s, for example, schizophrenia was generally attributed to "refrigerator mothers" and a chilly emotional climate in the patients' extended families. As of 2002, however, the application of computer models to schizophrenia indicates that the heritability of the disorder may be as high as 80%. Another instance is autism , which was also blamed at one time on faulty parenting but is now known to be 90+% heritable.

Mental disorders with organic causes

The two most important examples of mental disorders caused by organic changes or abnormalities in the brain are late-onset Alzheimer's disease and schizophrenia. Both disorders are polygenic, which means that their expression is determined by more than one gene. Another

disorder that is much less common, Huntington's disease, is significant because it is one of the few mental disorders that is monogenic, or determined by a single gene. SCHIZOPHRENIA. Researchers have known for many years that first-degree biological relatives of patients with schizophrenia have a 10% risk of developing the disorder, as compared with 1% in the general population. The identical twin of a person with schizophrenia has a 40% 50% risk. The first instance of a specific genetic linkage for schizophrenia, however, was discovered in 1987 by a group of Canadian researchers at the University of British Columbia. A case study that involved a Chinese immigrant and his 20-year-old nephew, both diagnosed with schizophrenia, led the researchers to a locus on the short arm of chromosome 5. In 1988, a study of schizophrenia in several Icelandic and British families also pointed to chromosome 5. Over the course of the next decade, other studies of families with a history of schizophrenia indicated the existence of genes related to the disorder on other chromosomes. In late 2001, a multidisciplinary team of researchers reported positive associations for schizophrenia on chromosomes 15 and 13. Chromosome 15 is linked to schizophrenia in European American families as well as some Taiwanese and Portuguese families. A recent study of the biological pedigrees found among the inhabitants of Palau (an isolated territory in Micronesia) points to chromosomes 2 and 13. Still another team of researchers has suggested that a disorder known as 22q deletion syndrome may actually represent a subtype of schizophrenia, insofar as people with this syndrome have a 25% risk of developing schizophrenia.

ALZHEIMER'S DISEASE. Late-onset Alzheimer's disease (AD) is unquestionably a polygenic disorder. It has been known since 1993 that a specific form of a gene for apolipoprotein E (apoE4) on human chromosome 19 is a genetic risk factor for late-onset Alzheimer's. People who have the apoE4 gene from one parent have a 50% chance of developing AD; a 90% chance if they inherited the gene from both parents. They are also likely to develop AD earlier in life. One of the remaining puzzles about this particular gene, however, is that it is not a consistent marker for AD. In other words, some people who have the apoE4 gene do not develop Alzheimer's, and some who do not have the gene do develop the disorder. In 1998, another gene on chromosome 12 that controls the production of bleomycin hydrolase (BH) was identified as a second genetic risk factor that acts independently of the apoE gene. In December 2000, three separate research studies reported that a gene on chromosome 10 that may affect the processing of amyloid-beta protein is also involved in the development of late-onset AD. There are two other forms of AD, early-onset AD and familial Alzheimer's disease (FAD), which have different patterns of genetic transmission. Early-onset AD is caused by a defect in one of three genes known as APP, presenilin-1, and presenilin-2, found on human chromosomes 21, 14, and 1, respectively. Early-onset AD is also associated with Down syndrome, in that persons with trisomy 21 (three forms of human chromosome 21 instead of a pair) often develop this form of Alzheimer's. The brains of people with Down syndrome age prematurely, so that those who develop early-onset AD are often only in their late 40s or early 50s when the symptoms of the disease first appear. Familial Alzheimer's disease appears to be related to abnormal genes on human chromosomes 21 and 14.

HUNTINGTON'S DISEASE. Huntington's disease, or Huntington's chorea, is a neurological disorder that kills the cells in the caudate nucleus, the part of the brain that coordinates movement. It also destroys the brain cells that control cognitive functions. In 1983, the gene that causes Huntington's disease was discovered on the short arm of human chromosome 4. Ten years later, the gene was identified as an instance of a triplet or trinucleotide repeat. Nucleotides are the molecular "building blocks" of DNA and RNA. Three consecutive nucleotides form a codon, or triplet, in messenger RNA that codes for a specific amino acid. In 1991, researchers discovered not only that nucleotide triplets repeat themselves, but that these repetitions sometimes expand in number during the process of genetic transmission. This newly discovered type of mutation is known as a dynamic or expansion mutation. Since 1991, more than a dozen diseases have been traced to expansion mutations. Eight of them are caused by repeats of the triplet cytosine-adenine-guanine (CAG), which codes for an amino acid called glutamine. In 1993, Huntington's disease was identified as a CAG expansion mutation disorder. Where the genetic material from a normal chromosome 4 has about 20 repeats of the CAG triplet, the Huntington's gene has a minimum of 45 repeats, sometimes as many as 86. The higher the number of CAG triplet repeats in a Huntington's gene, the earlier the age at which the symptoms will appear. The expansion mutation in Huntington's disease results in the production of a toxic protein that destroys the cells in the patient's brain that control movement and cognition.

Childhood developmental disorders

Developmental disorders of childhood are another large category of mental disorders caused by mutations, deletions, translocations (rearrangements of the arms of chromosomes) and other alterations in genes or chromosomes. TRIPLET REPEAT DISORDERS. Since 1991, expansion mutations have been identified as the cause of thirteen different diseases. Some, like Huntington's disease, are characterized by long expansion mutations of the trinucleotide sequence CAG, which in effect adds so much glutamine to the protein being synthesized that it becomes toxic to the nervous system. A second category of triplet repeat disorders contains extra triplets that add an amino acid called alanine to the protein. The sequence of nucleotides is cytosine-guanine-N, where N stands for any of the four basic nucleotides. Although the proteins produced by this type of expansion mutation are not toxic, their normal function in the body is disrupted. The developmental disorders related to these CGN triplets are characterized by abnormalities of the skeleton. One of these disorders is synpolydactyly, in which the patient has more than the normal number of fingers or toes. Another is cleidocranial dysplasia, a disorder marked by abnormal development of the skull. Other developmental disorders are caused by expansion mutations outside the regions of the gene that code for proteins. The segments of DNA that specify the sequence of a portion of a protein are known as exons, while the stretches of DNA that lie between the exons and do not code for proteins are called introns. The CAG and CGN groups of triplet disorders described in the preceding paragraph are expansion mutations that occur within exons. A third group of triplet disorders results from expansion mutations in introns. Expansions in this third group are usually much longer than those in the first two categories; some repeat several hundred or even several thousand times. The best-known expansion mutation in this group causes the disorder known as fragile X syndrome. Fragile X syndrome is the most common inherited form of mental

retardation and should be considered in the differential diagnosis of any child with developmental delays, mental retardation, or learning difficulties. The syndrome is caused by a large expansion of a cytosine-guanine-guanine (CGG) repeat which interferes with normal protein transcription from a gene called the FMR1 gene on the X chromosome. Males with the mutation lack a second normal copy of the gene and are more severely affected than females who have a normal FMR1 gene on their second X chromosome. In both sexes there is a correlation between the length of the expansion mutation and the severity of the syndrome. The discovery of expansion mutations was the solution to a long-standing genetic riddle. Clinicians had noticed as early as 1910 that some disorders produce a more severe phenotype or occur at earlier and earlier ages in each successive generation of an affected family. This phenomenon is known as anticipation, but its biological basis was not understood until recently. It is now known that triplet repeats that are long enough to cause disorders are unstable and tend to grow longer from generation to generation. For example, an expansion mutation of the cytosine-thymine-guanine (CTG) triplet causes a potentially life-threatening developmental disorder known as myotonic dystrophy. Repeats of the CTG triplet that are just above the threshold for myotonic dystrophy itself may produce a relatively mild disorder, namely eye cataracts in later life. Within two to three generations, however, the CTG repeats become longer, producing a fatal congenital illness. In addition to developmental disorders of childhood, expansion mutations may also be involved in other psychiatric disorders. Anticipation has been found in some families affected by bipolar disorder and schizophrenia, and some researchers think that it may also be present in some forms of autism. GENOMIC IMPRINTING. Another recent discovery in the field of biological psychiatry is the phenomenon of genomic imprinting, which distinguishes between chromosomes derived from a person's father and those derived from the mother. Genomic imprinting was discovered in the late 1980s as an exception to Gregor Mendel's laws of biological inheritance. A small subset of human genes are expressed differently depending on the parent who contributes them to a child's genetic makeup. This phenomenon has helped researchers understand the causation of three well-known genetic disorders Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes. In the 1980s, researchers studying Prader-Willi syndrome and Angelman syndrome noticed that both disorders were caused by a deletion on the long arm of chromosome 15 in the very same region, extending from 15q11 to 15q13. This finding was surprising, because the two syndromes have markedly different phenotypes. Children with Prader-Willi syndrome have severe mental retardation, poor muscle tone, small hands and feet, and a voracious appetite (hyperphagia) that begins in childhood. As a result, they are often obese by adolescence. Children with Angelman syndrome, on the other hand, do not speak, are often hyperactive, and suffer from seizures and sleep disturbances. In the late 1980s, advances in molecular genetics revealed that the different expressions of the same deletion on the same chromosome were determined by the sex of the parent who contributed that chromosome. Children with Prader-Willi syndrome had inherited their father's copy of chromosome 15 while the children with Angelman syndrome had inherited their mother's. Highly specific diagnostic tests for these two disorders have been developed within the past decade.

Beckwith-Wiedemann syndrome is an overgrowth condition in which patients develop abnormally large bodies. They often have low blood sugar at birth and are at high risk for developing Wilms tumor, a childhood form of kidney cancer. Beckwith-Wiedemann syndrome is caused by several different genetic mutations that affect imprinted genes on chromosome 11p15. One of these imprinted genes governs the production of a growth factor that is responsible for the children's large body size. BEHAVIORAL PHENOTYPES. Although medical professionals are familiar with the physical phenotypes associated with genetic disorders, the notion of behavioral phenotypes is still controversial. A behavioral phenotype is the characteristic set of behaviors found in patients with a genetic disorder. Behavioral phenotypes include patterns of language usage, cognitive development, and social adjustment as well as behavioral problems in the narrow sense. It is important for psychiatrists who treat children and adolescents to understand behavioral phenotypes, because they are better able to identify problem behaviors as part of a genetic syndrome and refer children to a geneticist for an accurate genetic diagnosis. Examples of behavioral phenotypes are those associated with Down, Prader-Willi, and Williams syndromes. Children with Down syndrome have an increased risk of developing early-onset Alzheimer's disease. They are usually quiet and good-tempered, but may also be hyperactive and impulsive. Their behavioral phenotype includes delayed language development and moderate to severe mental retardation. Children with Prader-Willi syndrome are often quiet in childhood but develop stubborn, aggressive, or impulsive patterns of behavior as they grow older. The onset of their hyperphagia is often associated with temper tantrums and other behavioral problems. They are typically obsessed with food, frequently hoarding it, stealing it, or stealing money to buy food. About 50% of children diagnosed with Prader-Willi syndrome meet the criteria for obsessive-compulsive disorder (OCD). Williams syndrome is a genetic disorder that results from a deletion of locus 23 on chromosome 7q11. Children with this syndrome often have an "elf-like" face with short upturned noses and small chins. Their behavioral phenotype includes talkativeness, friendliness, and a willingness to follow strangers. They are also hyperactive and easily distracted from tasks. The personality profile of children with Williams syndrome is so distinctive that many are diagnosed on the basis of the behavioral rather than the physical phenotype.