The strength of the genetic effect. Is there room for an environmental influence in the aetiology of schizophrenia
TL;DR: It is argued that a hypothesis combining genetic diathesis with environmental stress cannot be disproved, and it is also possible that 'non-genetic' factors consist entirely of stochastic events affecting gene expression or structure.
Abstract: The evidence for a genetic contribution to schizophrenia is compelling. However, the pattern of inheritance is complex and it is usually assumed that environmental factors also have a role that will eventually be identified. We argue that this is not necessarily the case. While a hypothesis combining genetic diathesis with environmental stress cannot be disproved, it is also possible that 'non-genetic' factors consist entirely of stochastic events affecting gene expression or structure.
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TL;DR: This work states that quantitative genetic research has built a strong case for the importance of genetic factors in many complex behavioral disorders and dimensions in the domains of psychopathology, personality, and cognitive abilities.
Abstract: Quantitative genetic research has built a strong case for the importance of genetic factors in many complex behavioral disorders and dimensions in the domains of psychopathology, personality, and cognitive abilities. Quantitative genetics can also provide an empirical guide and a conceptual framework for the application of molecular genetics. The success of molecular genetics in elucidating the genetic basis of behavioral disorders has largely relied on a reductionistic one gene, one disorder (OGOD) approach in which a single gene is necessary and sufficient to develop a disorder. In contrast, a quantitative trait loci (QTL) approach involves the search for multiple genes, each of which is neither necessary nor sufficient for the development of a trait. The OGOD and QTL approaches have both advantages and disadvantages for identifying genes that affect complex human behaviors.
939 citations
TL;DR: The five newest studies since 1995 from Europe and Japan have confirmed earlier findings on the genetic basis of clinical heterogeneity within schizophrenia and provided further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder.
Abstract: Twin studies have been vital for establishing an important genetic contribution to the etiology of schizophrenia. The five newest studies since 1995 from Europe and Japan have confirmed earlier findings. They yielded probandwise concordance rates of 41-65% in monozygotic (MZ) pairs and 0-28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80-85%. Twin studies are also valuable for investigating the etiological relationships between schizophrenia and other disorders, and the genetic basis of clinical heterogeneity within schizophrenia. Studies of discordant MZ pairs provide further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder. More recently, twin studies have begun to be used to directly investigate molecular genetic and epigenetic processes underlying schizophrenia.
881 citations
TL;DR: This neural diathesis-stress model is consistent with findings on prenatal factors and brain abnormalities in schizophrenia, and it provides a framework for explaining some key features of the developmental course and clinical presentation.
Abstract: There is a substantive literature on the behavioral effects of psychosocial stressors on schizophrenia. More recently, research has been conducted on neurohormonal indicators of stress responsivity, particularly cortisol release resulting from activation of the hypothalamic-pituitary-adrenal (HPA) axis. This article integrates the psychosocial and biological literatures on stress in schizophrenia, and it offers specific hypotheses about the neural mechanisms involved in the effects of stressors on the diathesis. Both the behavioral and biological data indicate that stress worsens symptoms and that the diathesis is associated with a heightened response to stressors. A neural mechanism for these phenomena is suggested by the augmenting effect of the HPA axis on dopamine (DA) synthesis and receptors. Assuming the diathesis for schizophrenia involves an abnormality in DA receptors, it is proposed that the HPA axis acts as a potentiating system by means of its effects on DA. At the same time, DA receptor abnormality and hippocampal damage render the patient hypersensitive to stress. This neural diathesis-stress model is consistent with findings on prenatal factors and brain abnormalities in schizophrenia, and it provides a framework for explaining some key features of the developmental course and clinical presentation.
842 citations
Book•
01 Nov 2009
TL;DR: It is tested whether significant differences in mental illness exist in a matched sample of Mental illness and the criminal justice system.
Abstract: We test whether significant differences in mental illness exist in a matched sample of Mental illness and the criminal justice system. In T. L. Scheid T. N. Brown (Eds.), A handbook for the study of mental health: Social contexts, theories. Find 9780521567633 A Handbook for the Study of Mental Health : Social Contexts, Theories, and Systems by Horwitz et al at over 30 bookstores. Buy, rent. A review of mental health problems in fathers following the birth of a child. for the study of mental health:Social contexts, theories, and systems (2nd ed., pp.
842 citations
TL;DR: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear.
Abstract: Background Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. Methods A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. Results A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. Conclusions Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.
777 citations
References
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Journal Article•
TL;DR: The Huntington's disease mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
6,992 citations
TL;DR: It is concluded that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of X-LINKED spinal and bulbar muscular atrophy.
Abstract: X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.
2,704 citations
TL;DR: Ch Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease, and genetic analysis yields a lod score of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-ONSet families and negative lod scores in familiesWith late-onsets disease.
Abstract: Human breast cancer is usually caused by genetic alterations of somatic cells of the breast, but occasionally, susceptibility to the disease is inherited. Mapping the genes responsible for inherited breast cancer may also allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-onset families and negative lod scores in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged between 2000:1 and greater than 10(6):1 on the basis of multipoint analysis of four loci in the region.
2,448 citations
TL;DR: The purpose of this paper is to suggest that the method developed in quantitative genetics for dealing with ‘threshold characters ’ is applicable to data on the incidence of diseases, and that by its use the authors can get further towards an answer to the question of the relative importance of heredity and environment.
Abstract: It is now commonly recognized that many diseases that are not inherited in a simple manner have, nevertheless, some hereditary basis. The evidence that heredity plays some part comes from the observation that the incidence of the disease is higher among the relatives of affected individuals than it is in the general population. An increased incidence among relatives does not, however, go far toward providing an amwer to the important question of how strong the hereditary factor is, because the difference of incidence has no simple genetic interpretation. The relative importance of heredity and environment in such a case is clearly a problem of quantitative genetics. The usual methods of quantitative genetics, however, are not immediately applicable because these are based on correlations between relatives in respect of some ‘graded’ character measurable on a continuous scale Data in the form of incidences refer, in contrast, to an ‘all-or-none’ classification; individuals either have the disease or they do not. Though the affected individuals may sometimes be graded according to the degree of severity of their symptoms, the normal individuals, who are the majority, cannot be graded by the degree of their normality. The purpose of this paper is to suggest that the method developed in quantitative genetics for dealing with ‘threshold characters ’ is applicable to data on the incidence of diseases, and that by its use we can get further towards an answer to the question of the relative importance of heredity and environment. (A fuller account of the method as applied in quantitative genetics will be found in Falconer, 1960.) The question of most general interest about the genetic causation of a disease that is not simply inherited is probably the relative importance of heredity as a causative agent. This questioii is meaningful only when stated in terms of amounts of variation; i.e. the variation between individuals that causes some to be affected and some not. What fraction of this variation is attributable to genetic differences between individuals? This fraction may be called the ‘degree of genetic determination ’. Unfortumtely the degree of genetic determination cannot be estimated from human data, unless possibly by the use of twins, but a related quantity, the heritability ’, can be estimated. The distinction between the degree of genetic determination and the heritability is as follows. Two kinds of genetic variation have to be distinguished, ‘additive’ and ‘non-additive’. The additiw genetic variance is attributable to the average effects of genes considered singly, as transmitted in the gametes. The non-additive genetic variance is attributable to the additional effects of these genes when combined in diploid genotypes. It therefore arises from dominance and interaction between genes at different loci ; if there is no dominance or interaction there can be no non-additive variance. The degree of
1,514 citations
"The strength of the genetic effect...." refers background in this paper
...Only those whose liability at some point exceeds a certain threshold manifest the disorder (Falconer, 1965; Reich et a!, 1972)....
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Book•
01 Jan 1988
TL;DR: This paper pointed out that "professors of philosophy who concern themselves with questions of justice and of practical rationality turn out to disagree with each other as sharply, as variously, and, so it seems, as irremediably upon how such questions are to be answered as anyone else".
Abstract: Modern academic philosophy turns out by and large to provide means for a more accurate and informed definition of disagreement rather than for progress toward its resolution. Professors of philosophy who concern themselves with questions of justice and of practical rationality turn out to disagree with each other as sharply, as variously, and, so it seems, as irremediably upon how such questions are to be answered as anyone else. They do indeed succeed in articulating the rival standpoints with greater clarity, greater fluency, and a wider range of arguments than do most others, but apparently little more than this. The only other type of resource generally available in our society to such persons is that which is supplied by participation in the life of one of those groups whose thought and action are informed by some distinctive profession of settled conviction with regard to justice and to practical rationality.
1,175 citations