The genetics of mental illness: implications for practice Steven E. Hyman1

Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or . Gone is the notion that there is a single gene that causes any or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients.

Keywords: mental disorders, genetics; ; mental disorders, drug therapy; genetic predisposition to disease; antipsychotic agents, therapeutic use.

Voir page 460 le re´sume´ en franc¸ais. En la pa´ gina 461 figura un resumen en espan˜ol.

Background cell, using one or several of the many receptor subtypes that exist for each neurotransmitter. For It is worth considering the complexity of the human example, the neurotransmitter serotonin has at least brain so as to put in perspective what is required of 14 different known subtypes of receptors. Neuro- genetic tools. The brain is the most complex object of transmitter receptors initiate complex signalling investigation in the history of biological science. Its cascades within nerve cells. These cascades process development depends on complex, often non-linear, information, produce immediate outputs, such as a gene–gene and gene-environment interactions, as decision to fire, and, at the same time, initiate long- well as on stochastic processes associated with the term, activity-dependent changes in the receiving interconnection of 100 000 million or more neurons. cells which may eventually lead to synaptic plasticity. As we are beginning to understand, the complexity of Each synapse is embedded in one or more neural the brain and the combinatorial interactions of many circuits that can be recruited or engaged with genes and non-genetic signals involved in building it exquisite specificity. In the basal ganglia, for example, are consistent with the richness of our mental lives a given neuron might fire in conjunction with a and behaviour. This complexity, however, has made particular movement made as part of a specific progress in the neuroscience and genetics of mental behavioural task, but not with the same movement illness exceedingly difficult. Each neuron in the brain when in a different behavioural situation (1). makes thousands of connections or synapses with The crowning complexity of the brain, how- neighbouring and distant neurons; there are probably ever, is that it is not static. Every time something new more than 100 trillion such connections, and across is learnt, whether a new name, a new skill or a new them each neuron may utilize several of more than emotional reaction, the active neurons alter the 100 chemical neurotransmitters. Signals encoded by synaptic architecture of the circuit in which the each neurotransmitter are decoded by the receiving learning has occurred. This process is termed plasticity; new synapses may be formed and old ones may be pruned; existing synapses may be strength- 1 Director, National Institute of , 6001 Executive ened or weakened. As a result, information is Boulevard, Room 8235, MSC 9669, Bethesda, MD 20892-9669, USA. processed differently. Ultimately, in ways not yet Ref. No. 00-0642 understood, our mental lives and behaviour are

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emergent properties of the firing patterns of neurons Genetics of behaviour within the parallel, distributed and potentially plastic circuits of our brains. and mental illness Diseases of the brain, whatever their patho- Genetic factors contribute to almost every human physiological basis, ultimately affect behaviour by disease by conferring susceptibility or resistance, and, altering the function of brain circuits. For example, if disease occurs, by influencing severity and stroke is an illness in which neurons die because of a progression. Because genes encode the building lack of oxygen. This event may create gaps in circuits blocks of cells, i.e. proteins, they should prove to be that traverse the damaged area or kill cells that give extremely powerful tools for research on mental rise to neural projections. The precise functional disorders. Gene discovery should have a transform- deficit depends on the circuits that have been ing influence on clinical practice. However, the disrupted and on the location. In most individuals, genetics of behavioural variation and of mental illness for example, information processing and important has proved enormously complex. This is consistent outputs required for the production of fluent speech with the intricate wiring of the brain and the wide come together in Broca’s area of the left hemisphere range of human behaviour, but means that the of the cerebral cortex. Stroke in this region often benefits of genetics for practice remain some years in causes a motor aphasia, but damage to other regions the future. of speech circuitry may produce related aphasic It is well established that the risk of mental symptoms. Despite the ability of the brain to adapt, illness runs in families. Family, twin and adoption brain diseases remind us that natural processes of studies have shown that, for schizophrenia, , plasticity are finite. In adults, only partial recovery manic depressive illness, major depression, attention from a Broca’s aphasia is the rule. In some situations, deficit hyperactivity disorder, panic disorder and such as in chronic neuropathic pain resulting from other mental illnesses, the transmission of risk is due nerve damage (2), the processes underlying plasticity to (9–13). How might this come about? can be subverted by illness or injury so as to produce DNA transmits information contained in the serious symptoms. Indeed, the pathogenesis of sequential order of its four nucleotide bases across addictive disorders (3) and post-traumatic stress generations and is the information repository that, in disorder (4) may represent the usurpation of normal interaction with environmental signals, controls the learning processes in reward and fear circuits development of an organism and the cells and organs respectively. within it. In cells, the information contained in DNA Just as specific neural circuitry underlies is transferred to proteins via other molecules primary sensory processes (e.g. vision or touch) and including structural RNA and messenger RNA. motor control, it is now recognized that specific Messenger RNA is translated to produce proteins, identifiable circuits underlie different aspects of which, for example, control the shapes of cells, cognition (5) and emotion (6, 7). Ultimately, under- regulate their chemical reactions and form neuro- standing the biological underpinnings of a disease like transmitter receptors and ion channels. With respect schizophrenia will be not simply a matter of finding to neural development, proteins form guidance cues several genes associated with the phenotype, measur- or controltheir synthesis; these direct the migration of ing neurotransmitter levels, or identifying a spot on a neurons to their correct places in the brain, leading to magnetic resonance imager. Rather, we must under- the establishment of appropriate connections. Other stand how a disease process disrupts the parallel proteins are required if the brain is to adapt in distributed processing that underlies relevant aspects response to environmental inputs associated, for of thinking, emotion and motivation (8). This will example, with drugs, injury or disease. Genes and require that function be understood at the molecular, their protein products are not the only factors cellular and systems levels and at the level of involved in establishing and consolidating the behavioural neuroscience. Eventually, however, it synaptic structure of the brain; the activity of synapses should be possible to ask how one version of a given themselves, partly resulting from experience, also gene (allele) contributes to the risk of depression or plays a vital role. Nonetheless, genes are critical to the schizophrenia while another, probably only a slightly development of the overall circuit maps and function different version, does not. It should also be possible of the brain. Variations in the DNA sequence of genes to ask when, in development, alleles that confer a risk may lead to the expression of an altered protein with of autism or schizophrenia are active, thus giving loss of function or with a new function that might be clues about the time of action of environmental adaptive, neutral or toxic to cells. Variations in DNA factors and information about when interventions sequences that regulate gene expression might alter might best take place. It may be that an allele the timing, cell type or spatial location in which a producing a risk of manic depressive illness, in protein is expressed. Variations in either protein combination with certain alleles occurring at other coding regions or regulatory regions of DNA might loci in the genome, is neutral or even advantageous in also result in a complete failure to express a protein. other combinations. Although we are still far from Sequence variants that affect behaviour, including the such achievements, it is already possible to chart risk of mental illness, must affect neurons in such a some important clinical implications of genetic way as to change the architecture, function or studies. adaptability of neural circuits in the brain.

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The goal of molecular genetic studies of mental disease, genes have been identified and cloned. In disorders is to identify and clone genes that addition to the technical difficulties of finding the contribute to the risk of such disorders, influence multiple alleles of small effect that characterize their course or promote resilience. However, the risk genetically complex disorders there are difficulties of mental disorders is genetically complex (14, 15). in defining phenotypes. For mental disorders this, Genetic complexity means that a trait such as indeed, may be the most difficult problem of all. vulnerability to a mental illness results not from a There are useful tools for communication (21, 22) single genetic defect but from the interaction of but it would be wrong to imagine that their criteria multiple genes. These gene–gene interactions need map on to the genome. These diagnostic systems not be simply additive; the function of one gene may describe a large number of putative disorders with be dependent on the prior function of one or more widely varying levels of validation. The refinement of other genes, a phenomenon known as epistasis (16). phenotypes and gene discovery may have to go hand- Moreover, even in combination, genes do not appear in-hand (23, 24). In the case of familial Alzheimer to fully determine the occurrence of a mental illness disease, genotypes have helped to clarify phenotypes but must interact with non-genetic factors. Indeed, and vice versa. studies of monozygotic twins, i.e. who have 100% of their DNA in common, performed in relation to schizophrenia and manic depressive illness (17), Strategies for progress confirm the requirement for non-genetic factors to convert vulnerability into illness. In no mental illness Given the difficulties described above, how can risk is there 100% concordance for the illness within genes for mental disorders be identified? How can we monozygotic twin pairs. Complexity may not end move beyond the current situation in which there with the need for multiple alleles at multiple loci in the have been no fully convincing replications of genetic genome or with the need for non-genetic factors: it is linkages in mental disorders? There is widespread possible that there is no single required allele for any agreement that progress in gene discovery requires mental disorder, i.e. different combinations of alleles the collection and analysis of one or more of the may influence vulnerability in different families. following types of data sets: Diseases due to a single major genetic locus, . large numbers of pedigrees from outbred popula- whether dominant or recessive, are often called tions containing multiple individuals affected with Mendelian disorders, Gregor Mendel having initially a given mental disorder; described the inheritance of traits due to the . pedigrees from genetically isolated populations; operation of single genes. In the human population . large numbers of affected individuals and control in general, deleterious mutations contributing to samples. Mendelian disorders are rare. Indeed, the genetics of the most common human disorders tend to be In outbred populations, large numbers of pedigrees complex, and include, in addition to mental disorders, are needed to provide sufficient statistical power to coronary artery disease, diabetes mellitus types I and detect the small effects of the multiple genes that II, and hypertension. It is likely that the alleles produce the risk of mental disorders. In isolated contributing to common complex disorders do not human populations a significant fraction of affected represent deleterious mutations, e.g. changes in individuals inherits a disease risk allele from a DNA nucleotide sequence that would markedly common ancestor. In addition to the benefit of damage a protein, but that they are genetic variants reduced genetic heterogeneity, all affected indivi- that in some combinations are neutral or even duals may be treated as distant relatives. Considerable advantageous (thus explaining their high population genetic information can be obtained by considering frequency), only producing a disease risk in certain not only the generation of probands (identified unfortunate combinations. There are rare Mendelian affected individuals) but also all family relationships disorders with mental symptoms, e.g. Rett syndrome, in the history of a population. A third data set for gene in which symptoms resembling those of autism discovery is based on the collection of genetic coexist with mental retardation (18), and there are material from large numbers of affected individuals rare Mendelian forms of early-onset familial Alzhei- and their parents or other suitable controls. These mer disease (19). The identification of such Mende- data may be used to evaluate so-called candidate lian forms, even though they may be responsible for genes that are thought to play a role in gene only a small percentage of cases within a population, pathophysiology. Given the complexity of the brain e.g. of Alzheimer disease, is potentially very and the current state of knowledge it is not surprising important as a research tool. No rare Mendelian that the number of compelling candidate genes is forms of the common mental disorders have yet been quite small. As a result of advances in technology, detected. such as high-throughput analytical and molecular It is far easier to identify a genetic locus that methods, it should be possible to test every human contributes very large effects on phenotype than to gene as a possible candidate gene for the production identify multiple loci where each contributes a small of risk of mental disorders, or, indeed, any other effect (20). For almost all the important Mendelian phenotype of interest. disorders, such as cystic fibrosis and Huntington

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The National Institute of Mental Health, complexity of risk of mental disorders. Thus there is Bethesda, is funding large collaborative projects in substantial comorbidity between depression and China, the Eastern Mediterranean, Europe, Latin certain anxiety disorders and there is comorbidity America, and the USA, as well as studies of isolated between tic disorders and obsessive–compulsive populations in the Azores, Micronesia, the Russian disorder. Moreover, some clinically important disease Federation, and South Africa. An important aspect of variants, such as rapid cycling , do not the Institute’s approach to human genetics research is breed true within families. This picture is consistent that investigators should eventually place their DNA with the complexity of genetic risk. It may be that samples and phenotypes in the public domain. In this what maps on to the genome will prove to be simpler way, as new ideas become available, it should be clusters of symptom complexes than those in the possible to test them rapidly. Thus the data sets current diagnostic manuals, or perhaps risk that can should be available for future studies as the be converted into depression, an or technologies for genotyping and the statistical both, depending on the presence of modifier genes or analysis of complex data sets (25) mature (see of certain life experiences. It is also possible that what http://www-grb.nimh.nih.gov/gi.html). Develop- maps best on the genome is not symptom clusters but ing statistical and molecular approaches for efficient underlying neurobiological differences, sometimes genome-wide studies of gene variants should greatly referred to as endophenotypes. Such phenotypes benefit from the availability of such archived currently being used in genetic studies include materials. A similar effort is now under way in the abnormalities in eye movements which are associated United Kingdom to develop collections of well- with schizophrenia (28). However, as advances in characterized DNA samples of genetically complex cognitive neuroscience and take place, disorders having a significant impact on public health phenotypes based on patterns of brain activity or (see http://www.mrc.ac.uk/welcome.htm). neurochemical differences may emerge. The dis- The critical technological platforms for facil- covery of disease vulnerability genes should be an itating gene discovery are the completion of the important step in helping to resolve the boundaries of international and parallel some disease entities and to understand the precise projects within industry, revealing the sequence of nature of risk transmitted within families. Interest- the human genome, and multiple international ingly, these discoveries may not yield diagnostic tests projects aimed at identifying variation in all human that are generally useful in screening diverse popula- genes. The variations that are the focus of most tions. Depending on the number of loci required for a current large-scale efforts are DNA sequence particular mental illness phenotype and the degree to variations in which a single nucleotide base is altered, which there is heterogeneity among the loci i.e. single-nucleotide polymorphisms (26). These contributing to illness in different families, tests represent the most common polymorphisms in the may be cumbersome, requiring multiple family human genome. Because of their abundance and members and genotypes at multiple loci. Given the wide distribution across the genome, as well as their importance of non-genetic factors in disease expres- potential for large-scale automated sequence analysis sion, the predictive value of genetic tests may also (genotyping) using DNA microarrays (DNA chips) prove to be poor. Because of the difficulty and or mass spectrometry, single-nucleotide polymorph- imprecision of predictive genetic screens, their value isms are likely to prove extremely useful for genetic in high-risk families may only outweigh the problems studies of complex diseases. New mathematical after effective preventive interventions are devel- methods are being developed to analyse genotypes oped. at many loci in whole-genome studies, whereby associations may be detected between single-nucleo- Impact of genetics on the development tide variants and the presence of a trait of treatment such as a mental disorder (27). The availability of large The concept of a drug target, i.e. a molecular target DNA and phenotype collections, catalogues of against which compounds can be tested for inhibitory human genetic variation, and mature genotyping or facilitative activity, is central to modern processes and analytic technologies should eventually permit of drug development. In , the identification the identification of genes that produce risk for of effective drug treatments began with a series of mental disorders. serendipitous discoveries, firstly of lithium (29) and later of chlorpromazine, the first antipsychotic drug, and imipramine and the monoamine oxidase inhibi- Clinical implications of genetics tors, the first antidepressant compounds. Epidemiology As was the rule during the 1950s, the actual molecular targets of antipsychotic and antidepressant Since the beginning of the modern era of psychiatric drugs became known only after the drugs were found diagnosis it was hoped that symptom clusters to be efficacious. The precise molecular target of defining syndromes, courses of illness, family history lithium remains a matter of debate, although there are and perhaps treatment response would coalesce into at least two highly compelling candidates. The D2 valid disease entities. This simple picture has proved dopamine receptor family and the serotonin 2a invalid in the light of present knowledge of the

458 Bulletin of the World Health Organization, 2000, 78 (4) The genetics of mental illness

(5-HT2a) receptor were identified as molecular are ultimately secreted these protein-cleaving en- targets for antipsychotic drug development on the zymes are referred to as the a-, b- and g-secretases. If basis of the efficacy of existing antipsychotic drugs the b-amyloid precursor is cleaved by the a-secretase, and the properties of clozapine respectively. In the the resulting fragment is not pathogenic. The action case of antidepressant drugs, the monoamine of the b- and g-secretases, together releasing the Ab reuptake transporters, most notably the norepine- fragment, may lead to amyloid deposition. The little phrine and serotonin reuptake transporters, were understood g-secretase may be presenilin 1 or closely identified as drug targets. More recently a host of associated with it. The mutations that produce early- other synaptic proteins within noradrenergic, ser- onset familial Alzheimer disease bias these processes otonergic and dopaminergic synapses have been toward the production of pathogenic Ab fragments. identified as potential targets for the development of It now appears likely that other genetic variants that antidepressant drugs. As a result of the exploitation have been implicated in late-onset Alzheimer disease, of these molecular targets by the pharmaceutical such as ApoE4 and certain a2-macroglobulin alleles, industry, antipsychotic drugs have been developed may affect the metabolism of b-amyloid and its which may have enhanced efficacy, and new cleavage products. This has led to an intense race antipsychotic and antidepressant drugs are available among pharmaceutical companies to produce in- that have milder side-effects than older compounds. hibitors of the b- and g-secretases. These treatments represent real advances but there is Although the b-amyloid story has yet to be a great need for fundamentally new treatments confirmed, these two secretase molecules have directed at the actual pathophysiology of mental become important drug targets whose inhibition, disorders and perhaps capable of preventing the very significantly, would interrupt the pathogenesis onset or progression of disease or of effecting cures. of Alzheimer disease. Should the story prove correct, Thus the goal for the development of treatment is to and should safe and effective inhibitors be found, move from drug targets derived from the action of powerful new weapons would be available for existing treatments to targets related to pathophy- altering the course of or even preventing Alzheimer siological processes. This is perhaps the greatest disease. promise of genetics and neuroscience. Consider, for The genetics of the most common mental example, genetic discoveries that may lead to new disorders appears more complex than that character- treatments for Alzheimer disease. Success is not izing early-onset Alzheimer disease families, which certain but there are some very promising leads that led to the breakthroughs outlined above. None- illustrate the power of neuroscience and genetics to theless, through the discovery of vulnerability genes identify drug targets involved in the fundamental it is conceivable that indications will be obtained of disease process. The result could be treatments that pathogenic pathways where direct intervention in would slow or halt progression of the disease. those processes becomes possible. Improved timing Much research in biochemistry, genetics and of interventions should be achievable if it proves neurobiology has suggested that a small fragment of possible to determine when, in development, these the b-amyloid precursor protein (a specific form of genes are active. the so-called Ab fragment) may be one of the causes Genetics also offers the prospect of individua- of cell death in Alzheimer disease. A large amount of lized treatments by predicting which patients might biochemical research led to the identification of this give a good response to a drug, or, more probably, fragment but the major breakthroughs came from which might experience serious side-effects. Phar- genetics. The common varieties of Alzheimer disease macogenetics focuses on genes that affect the actions appear to be genetically complex, i.e. resulting from of many drugs used to treat clinical disease. multiple genes (including the ApoE locus) and non- Mutations in a given gene lead to variations in the genetic factors. However, a small percentage of amount of a protein that is synthesized, its properties familial Alzheimer disease of early onset results from and its final destination. Such genetic mutations may Mendelian transmission, i.e. in these cases the produce a variant protein that can cause an altered dominant inheritance of a single locus is sufficient drug response. One early clinical application would to produce illness. studies in early- be in genetic testing to determine a person’s onset families identified multiple mutations in three cytochrome P-450enzyme genotypes. Different different genes: the b-amyloid precursor itself and versions of these enzymes that are critical to drug genes encoding the previously unknown proteins metabolism in the liver would influence dosing with presenilin 1 and presenilin 2. or tolerance of different drugs. Ultimately, one of the It appears that the b-amyloid precursor protein greatest benefits from genetic research may come can be cleaved in three positions to produce different from understanding the genetic contributions to smaller fragments that are then released into the individual-specific drug action. extracellular space, where, under normal circum- stances, they may be involved in cellular growth and maintenance. However, one fragment, the Ab Conclusion peptide, has a tendency to precipitate out and form pathogenic amyloid deposits. Each cleavage site Through the integration of information coming from involves a different protease, and since the fragments genes, molecules and cells with that flowing from the

Bulletin of the World Health Organization, 2000, 78 (4) 459 Special Theme – Mental Health

environment and experience to the brain’s neuronal tric Association Diagnostic and Statistical Manual to circuits, neuroscience can be expected to revolutio- the investigation of disease risk. This would lead to nize clinical practice. In the immediate future it is benefits for primary, secondary and tertiary preven- necessary to obtain genetic resources from well- tion and for the timing of treatment. Breakthroughs defined pedigrees that are readily accessible to all in preventive and treatment interventions should investigators, while building the technological plat- come from progress in genetics research and form needed to transform these resources into neuroscience. Information on how variations in the cloned risk-conferring genes. Major steps can be DNA nucleotide sequence of genes can alter not only expected to hinge on the imminent availability of a the function, but also the timing, cell type or spatial reference human genome sequence, at least in draft location in which gene products are expressed, and, in form, and on an extensive catalogue of genetic turn, how neural circuits are built, should provide variation in the form of single-nucleotide polymorph- critical tools for understanding how the particular isms, both produced by international public and architecture or adaptability of specific neural circuits private efforts. The eventual identification of risk- may affect behaviour. Although the identification, conferring genotypes at certain loci should provide cloning and characterization of the functions of informative independent variables capable of revo- disease vulnerability genes have proved more lutionizing the ability to classify mental disorders. By difficult than was once envisaged, strategies for combining a knowledge of gene function with the fulfilling these tasks are emerging, with potentially search for modifiable environmental risk factors, it rich benefits for clinical practice. n should be possible to contribute towards a refocusing of from counting indivi- Acknowledgements duals with syndromes defined by the International The author thanks Paul Sirovatka, Steven Moldin and Classification of Diseases or the American Psychia- Hemin Chin for invaluable help with the manuscript.

Re´ sume´ Ge´ne´ tique et maladie mentale : incidences sur la pratique La ge´ne´tique mole´culaire et, plus particulie` rement, difficile que de de´couvrir les causes des maladies l’identification des ge`nes responsables de la vulne´rabilite´ monoge´niques. C’est la raison pour laquelle le National a` la maladie mentale, renferme un e´ norme potentiel, Institute of Mental Health des Etats-Unis d’Ame´rique a qu’il s’agisse de comprendre la physiopathologie des e´norme´ment investi dans ce domaine, comme l’ont fait le troubles mentaux, d’e´ laborer une nouvelle e´pide´miolo- Medical Research Council au Royaume-Uni et d’autres gie des troubles mentaux axe´e sur le risque ou de organismes. L’un des objectifs du National Institute of de´couvrir des traitements pour gue´rir, et meˆmepre´venir, Mental Health est de constituer de tre`s nombreuses ces maladies incapacitantes, souvent mortelles. Cepen- collections d’ADN et de recueillir les donne´es corres- dant, si l’on veut tirer pleinement parti de la ge´ne´tique, il pondantes sur le phe´notype, tout en assurant la faut au minimum se fixer pour but l’identification, le protection approprie´e des sujets humains, collections clonage et la caracte´ risation fonctionnelle des ge`nes de que tous les chercheurs pourront utiliser une fois preˆtle vulne´rabilite´a` la maladie. Cette taˆ che s’est re´ve´le´eplus support technique permettant l’analyse des troubles difficile qu’on ne le pensait commune´ment il y a dix ans. complexes. Ce support inclut le projet international sur le Aucun variant ge´ne´tiquement simple, c’est-a` -dire de ge´nome humain et les initiatives prive´es de´ploye´es en type mende´lien, des principales maladies mentales n’a paralle`le pour e´tablir le se´quenc¸age de tout le ge´nome e´te´ mis en e´ vidence. Les e´tudes sur les jumeaux et les humain. Elle comprend e´galement les initiatives pu- e´tudes cherchant a`e´tablir un lien entre le risque de bliques et prive´ es qui visent a` dresser des catalogues maladie et leur localisation chromosomique re´ve` lent la utiles des variantes des se´quences humaines ; s’y complexite´ge´ne´tique des maladies mentales. Aussi, ajoutent les tentatives faites pour mettre au point, pour contrairement a` la chore´e de Huntington ou aux rares la recherche des geˆnes de risque, des me´thodes de formes familiales de la maladie d’Alzheimer, aucun ge`ne ge´notypage a` haut rendement et peu couˆ teuses et des n’est a` l’origine a` lui seul des troubles de l’humeur, de me´ thodes d’analyse statistique applique´es a`lage´ne´- l’anxie´te´ ou de la schizophre´ nie. Ces maladies semblent tique sensiblement ame´ liore´es. en fait re´sulter de l’interaction entre des locus nombreux Pour comprendre comment les ge`nes interagissent agissant ensemble et des facteurs non ge´ne´tiques. avec les facteurs non ge´ne´tiques (facteurs de de´veloppe- Cette difficulte´ est accrue du fait de l’he´te´roge´- ment stochastiques et facteurs environnementaux ne´ite´ sous-jacente des phe´notypes qui pourraient eˆtre spe´ cifiques) pour construire le cerveau et de´boucher sur identifie´s d’apre`s les crite`res de la Classification un risque de diffe´rentes maladies mentales, des internationale des maladies ou du manuel diagnostique recherches sont ne´cessaires a` divers niveaux des et statistique des troubles mentaux (DSM) de l’American neurosciences cognitives – mole´cules, cellules et syste`me Psychiatric Association. Identifier des variants ge´ne´tiques – ainsi qu’au niveau des sciences du comportement. En multiples situe´s dans des locus distincts du ge´ nome, dont raison de la complexite´ des proble`mes que pose chacun augmenterait un peu le risque ou meˆme l’architecture ge´ne´tique du comportement, les mode`les interagirait non line´ airement, serait beaucoup plus algoristiques et l’informatique sont e´galement mis a`

460 Bulletin of the World Health Organization, 2000, 78 (4) The genetics of mental illness contribution. Vu qu’il faut faire appel a` plusieurs modifier la fonction mais e´galement agir sur l’expression disciplines pour e´lucider la complexite´ structurelle et d’une prote´ine – moment, type cellulaire et localisation fonctionnelle du cerveau, son de´veloppement, sa de la production – les chercheurs peuvent entrevoir plasticite´eta` sa capacite´a`e´voluer au cours de la vie, comment les variants des se´quences qui influent sur on peut s’attendre a` ce que la ge´ne´ tique devienne un outil l’architecture ou l’adaptabilite´ des neurocircuits peuvent de recherche de plus en plus puissant. Il devrait en re´sulter influer sur le comportement. des changements profonds dans la pratique clinique. L’une des principales applications de la ge´ne´tique La complexite´e´vidente au niveau ge´ne´ tique fait mole´culaire a` la mise au point du traitement des ressortir un aspect que les cliniciens connaissent depuis maladies mentales est la capacite´ d’identifier des longtemps : l’extraordinaire he´te´roge´ne´ ite´ des entite´s produits ge´niques susceptibles de servir de cibles diagnostiques pre´sume´es de nos manuels diagnostiques mole´culaires aux me´dicaments ou aux autres interven- actuels. Si l’on pouvait connaıˆtre le ge´notype de certains tions visant directement certains processus physiopa- locus et le conside´rer comme une variable inde´ pendante, thologiques. Les recherches sur la maladie d’Alzheimer la classification des maladies mentales serait facilite´e.En illustrent la taˆchea` venir. Apre`s avoir identifie´ plusieurs associant la connaissance de la fonction des ge`nes et la ge`nes de risque sur un sous-type mende´lien de la recherche de facteurs de risque environnementaux maladie, dit forme familiale pre´coce de la maladie modifiables, il devrait eˆtre possible d’aider a` recentrer d’Alzheimer, les chercheurs ont de´couvert que certaines l’e´pide´miologie psychiatrique sur le risque, et donc sur la enzymes de clivage des prote´ines, ou prote´ases, possibilite´depre´venir l’apparition et l’e´volution de la semblaient capables de produire des fragments toxiques maladie ou de l’incapacite´. du produit, par ailleurs be´nin, des ge`nes de risque, a` Les progre`s continus de la recherche ge´ne´tique savoir le pre´curseur de la prote´ine beˆta-amyloı¨de. Cette devraient de´boucher sur des avance´es the´ rapeutiques de´couverte a suscite´unde´ ploiement intensif d’activite´s importantes. Les chercheurs sont de plus en plus pour mettre au point des inhibiteurs des prote´ ases conscients de l’influence de l’ADN sur la structure et le dangereuses. Si la ge´ne´ tique des troubles mentaux est fonctionnement des cellules et de leurs principaux outils, beaucoup plus complexe que celle de la forme familiale les prote´ines, et de la fac¸on dont celles-ci dirigent ou pre´coce de la maladie d’Alzheimer, les strate´ gies de la influencent a` leur tour le de´ veloppement du syste`me ge´ne´tique mole´ culaire sont e´galement applicables a`la nerveux qui conduit a` la constitution des circuits recherche d’une approche directe de la physiopathologie complexes du cerveau. Sachant que la variation des des troubles mentaux, de leur traitement, de leur se´quences nucle´ otidiques de l’ADN peut non seulement gue´rison et de leur pre´vention.

Resumen Gene´ tica de las enfermedades mentales: implicaciones pra´ cticas La gene´tica molecular, y ma´ s concretamente la Esa dificultad se ve agravada por la heterogenei- identificacio´ n de genes causantes de vulnerabilidad a dad de los fenotipos que podrı´an identificarse con las enfermedades mentales, abre grandes posibilidades arreglo a los criterios de la Clasificacio´ n Internacional de de entender la fisiopatologı´a de las enfermedades Enfermedades o del Manual Diagno´ stico y Estadı´stico de mentales, disen˜ ar una nueva epidemiologı´a de esas las Enfermedades Mentales de la Asociacio´ n Americana enfermedades centrada en el riesgo y conseguir de Psiquiatrı´a. La identificacio´ n de mu´ ltiples variantes tratamientos que permitan curar o incluso prevenir gene´ticas en distintos loci del genoma, que puedan estas dolencias discapacitantes y a menudo mortales. contribuir a incrementar ligeramente el riesgo, cuando Sin embargo, para lograr el ma´ ximo beneficio de la no interaccionen de manera no lineal, resultara´ mucho gene´tica, el objetivo deberı´a ser como mı´nimo ma´ s difı´cil que descubrir las causas de trastornos identificar, clonar y caracterizar funcionalmente los monoge´nicos. En consecuencia, el Instituto Nacional genes que determinan la vulnerabilidad a las enferme- de Salud Mental de los Estados Unidos ha hecho dades. La tarea ha resultado ma´ s ardua de lo que inversiones considerables en ese terreno, al igual que el muchos creı´an hace una de´cada. No se ha hallado Consejo de Investigaciones Me´dicas del Reino Unido y ninguna variante gene´ticamente simple, es decir, otros organismos. Uno de los objetivos del Instituto mendeliana, de los trastornos mentales ma´ s graves. Nacional de Salud Mental es crear un gran repertorio de Los resultados de los estudios realizados con gemelos y secuencias de ADN y de la informacio´ n fenotı´pica de los trabajos de asociacio´ n del riesgo de enfermedad correspondiente – observando siempre los sistemas de a determinadas regiones cromoso´ micas muestran que proteccio´ n establecidos para los trabajos con sujetos las enfermedades mentales son gene´ticamente com- humanos – al que puedan acceder todos los cientı´ficos, plejas. Ello significa que, a diferencia de la enfermedad para cuando se ultime la plataforma tecnolo´ gica que ha de Huntington o de raras variantes familiares de la de permitir determinar el origen de trastornos complejos. enfermedad de Alzheimer, no hay ningu´ n gen que por sı´ Dicha plataforma incluye el Proyecto Genoma Humano, solo cause trastornos del estado de a´nimo o de de a´ mbito internacional, y actividades privadas paralelas ansiedad o esquizofrenia. Antes bien, estas enferme- que persiguen la secuenciacio´ n completa de los genes dades parecen ser el resultado de la interaccio´n de humanos. Incluye tambie´n las actividades pu´ blicas y muchos loci gene´ticos con factores no gene´ticos. privadas emprendidas para crear cata´ logos de utilidad de

Bulletin of the World Health Organization, 2000, 78 (4) 461 Special Theme – Mental Health

las variaciones de esas secuencias, proyectos de Los continuos avances de las investigaciones desarrollo de me´ todos de genotipificacio´ n de bajo costo gene´ticas deberı´an conducir a importantes innovaciones y alto rendimiento, y me´todos gene´ticos estadı´sticos muy terape´uticas. Los investigadores son cada vez ma´s mejorados para la deteccio´ n de genes de riesgo. conscientes de la influencia del ADN en la estructura y Para entender co´ mo interaccionan los genes con funcio´ n de las ce´lulas y de sus principales herramientas, factores no gene´ticos (incluidos aquı´ tanto factores las proteı´nas, y de co´ mo, a su vez, las proteı´nas dirigen o estoca´ sticos que actu´ an durante el desarrollo como influencian los procesos de desarrollo neural que factores ambientales especı´ficos) para configurar el determinan los complejos circuitos cerebrales. Sabiendo cerebro y crear predisposicio´ n a diferentes enfermedades que las variaciones de la secuencia nucleotı´dica de los mentales, es necesario realizar investigaciones a genes pueden influir no so´ lo en su funcio´ n sino tambie´n distintos niveles, por ejemplo a nivel molecular, celular en el momento, el tipo de ce´lula o el lugar del organismo ydesistemasenelcampodelasneurociencias en que esa funcio´ n se exprese, los investigadores pueden cognitivas, y a nivel de las ciencias del comportamiento. empezar a desentran˜ ar de que´ manera pueden incidir en Debido a la complejidad de los problemas que plantea la el comportamiento esas variantes que afectan a la arquitectura gene´tica del comportamiento, entran arquitectura o la adaptabilidad de los neurocircuitos. tambie´n en juego la informa´ tica y los modelos Una aplicacio´ n clave de la gene´tica molecular para computacionales. Dada la multiplicidad de disciplinas el desarrollo de tratamientos contra las enfermedades implicadas en la elucidacio´ n de la complejidad estructu- mentales consiste en la posibilidad de identificar ral y funcional del cerebro, de su desarrollo y de su productos de los genes que puedan utilizarse como plasticidad o capacidad para evolucionar a lo largo de la dianas de medicamentos u otras intervenciones dirigidas a vida, cabe prever que la gene´tica se convertira´enun procesos fisiopatolo´ gicos especı´ficos. Las investigaciones arma de investigacio´ n cada vez ma´ s poderosa, y ello sobre la enfermedad de Alzheimer ilustran la tarea que nos transformara´ profundamente la pra´ ctica clı´nica. espera. Despue´s de identificar varios genes de riesgo en un La notoria complejidad observada a nivel gene´ tico subtipo mendeliano de la enfermedad, el denominado abunda en algo que los investigadores clı´nicos Alzheimer familiar de aparicio´ n precoz, diversos investi- constataronyahacetiempo,asaber,laenorme gadores descubrieron que algunas enzimas de escisio´nde heterogeneidad de las posibles entidades diagno´ sticas proteı´nas, o proteasas, podı´an al parecer producir presentadas en los manuales diagno´ sticos. El hecho de fragmentos to´ xicos del producto normalmente benigno poder disponer por fin de genotipos de determinados loci de los genes de riesgo, esto es, la proteı´na precursora del como variables independientes deberı´a permitirnos beta-amiloide. Este descubrimiento ha dado lugar a una clasificar mejor las enfermedades mentales. La combi- intensa actividad para desarrollar inhibidores de esas nacio´ n del conocimiento de la funcio´ n de los genes y la peligrosas proteasas. Aunque la gene´tica de los trastornos bu´ squeda de factores de riesgo ambientales modificables mentales comunes es mucho ma´ s compleja que la de la habra´ de contribuir a reorientar la epidemiologı´a enfermedad de Alzheimer familiar de aparicio´ n precoz, las psiquia´ trica hacia el concepto de riesgo y, por estrategias de gene´tica molecular se pueden aplicar consiguiente, hacia la posibilidad de prevenir la aparicio´n igualmente a la bu´ squeda de un punto de intervencio´n o el agravamiento de las enfermedades o las discapa- directa en la fisiopatologı´a de las enfermedades mentales, cidades conexas. ası´ como en su tratamiento, curacio´ n y prevencio´n.

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