Gene-environment Interplay Research Articles

Gene-environment interplay in alcoholism and other substance abuse disorders: expressions of heritability and factors influencing vulnerability.

Factors that confer predisposition and vulnerability for alcoholism and other substance abuse disorders may be described usefully within the gene-environment interplay framework. Thus, it is postulated that heritability provides a major contribution not only to alcohol but also to other substances of abuse. Studies of evoked potential amplitude reduction have provided a highly suitable and testable method for the assessment of both environmentally-determined and heritable characteristics pertaining to substance use and dependence. The different personal attributes that may co-exist with parental influence or exist in a shared, monozygotic relationship contribute to the final expression of addiction. In this connection, it appears that personality disorders are highly prevalent co-morbid conditions among addicted individuals, and, this co-morbidity is likely to be accounted for by multiple complex etiological relationships, not least in adolescent individuals. Co-morbidity associated with deficient executive functioning may be observed too in alcohol-related aggressiveness and crimes of violence. The successful intervention into alcohol dependence and craving brought about by baclofen in both human and animal studies elucidates glutamatergic mechanisms in alcoholism whereas the role of the dopamine transporter, in conjunction with both the noradrenergic and serotonergic transporters, are implicated in cocaine dependence and craving. The role of the cannabinoids in ontogeny through an influence upon the expression of key genes for the development of neurotransmitter systems must be considered. Finally, the particular form of behaviour/characteristic outcome due to childhood circumstance may lie with biological, gene-based determinants, for example individual characteristics of monoamine oxidase (MAO) activity levels, thereby rendering simple predictive measures both redundant and misguiding.

The interplay of nature, nurture, and developmental influences: the challenge ahead for mental health.

This article succinctly reviews research achievements in the fields of psychiatric genetics, psychosocial influences on mental disorder, and developmental processes. The challenges for the future are discussed in relation to finding and understanding the following: (1) susceptibility genes; (2) environmentally mediated causal risk processes; (3) nature-nurture interplay; (4) the effects of psychosocial adversity on the organism; (5) the causal processes responsible for group differences in rates of disorder; and (6) age-related changes in psychopathological characteristics.

Effects of genetic background on neonatal Borna disease virus infection-induced neurodevelopmental damage: II. Neurochemical alterations and responses to pharmacological treatments

The gene–environment interplay is thought to determine variability in clinical conditions and responses to therapy in human neurodevelopmental disorders. Studying abnormal brain and behavior development in inbred strains of rodents can help in the identification of the complex pathogenic mechanisms of the host–environment interaction. This paper is the second one in a series of the two reports of the use of the Borna disease virus (BDV) infection model of neurodevelopmental damage to characterize effects of genetic background on virus-induced neurodevelopmental damage in inbred rat strains, Lewis and Fisher344. The present data demonstrate that neonatal BDV infection produced regional and strain-related alterations in levels of serotonin, norepinephrine and in levels of serotonin turnover at postnatal day 120. Neonatal BDV infection also induced upregulation of hippocampal 5-HT 1a and cortical 5-HT 2a receptors in Lewis rats and downregulation of cortical 5-HT 2a receptors in Fisher344 rats. BDV-associated regional downregulation of D 2 receptors and dopamine transporter sites were noted in Fisher344 rats. In addition to the neurochemical disturbances, neonatal BDV infection induced differential responses to serotonin compounds. While 8-OH-DPAT suppressed virus-enhanced ambulation in BDV-infected Fisher344, fluoxetine inhibited virus-induced hyperactivity in BDV-infected Lewis rats only. The present data provide new insights into the pathogenic events that lead to differential responses to pharmacological treatments in genetically different animals following exposure to the same environmental challenge.

Gene—environment interplay in relation to emotional and behavioural disturbance

▪ Abstract The conceptual and methodological issues involved in the study of gene-environment correlations (rGE) and interactions (GxE) are discussed in historical context. Quantitative genetic findings are considered with respect to rGE and GxE in relation to emotional and behavioral disturbance. Key conceptual and substantive implications are outlined in relation to both genetic and environmental risk mediation, with a brief note on evolutionary considerations.

Gene-environment interplay in relation to emotional and behavioral disturbance.

The conceptual and methodological issues involved in the study of gene-environment correlations (rGE) and interactions (GxE) are discussed in historical context. Quantitative genetic findings are considered with respect to rGE and GxE in relation to emotional and behavioral disturbance. Key conceptual and substantive implications are outlined in relation to both genetic and environmental risk mediation, with a brief note on evolutionary considerations.

Gene-Environment Interplay in Oppositional Defiant and Conduct Disorder

Oppositional defiant and conduct disorder is a disturbance in behavior that is characterized by aggressive and antisocial acts. At present, genetic research on conduct disorder has raised more questions than it has answered, and basic questions such as the heritability of childhood antisocial behavior cannot yet be answered with certainty. Current research, however, has consistently highlighted the importance of gene-environment interplay in antisocial behavior.

Developmental psychopathology: concepts and challenges.

The defining features of developmental psychopathology concepts include attention to the understanding of causal processes, appreciation of the role of developmental mechanisms, and consideration of continuities and discontinuities between normality and psychopathology. Accomplishments with respect to these issues are reviewed in relation to attachment disorders, antisocial behavior, autism, depressive disorder, schizophrenia, and intellectual development. Major research challenges remain in relation to measurement issues, comorbidity, gender differences, cognitive processing, nature-nurture interplay, heterotypic continuity, continuities between normal variations and disorders, developmental programming, and therapeutic mechanisms in effective treatments.

Abnormal blood lipids: is it environment or is it genes?

Genetic and environmental factors contribute to the development and progression of atherosclerotic coronary heart disease processes. Major independent risk factors for coronary heart disease, including adverse levels of plasma lipids and lipoproteins, are also influenced by genetic and potentially modifiable environmental factors. Recent advances in molecular biology have resulted in the identification of specific genes associated with lipid disorders. The complex gene-environment interplay that contributes to interindividual variation in components of the lipid profile is also partially clarified. This article provides an overview of available data on the genetic and environmental influences on lipids and lipoproteins with emphasis on implications for clinical practice and future research.

Genetics and Child Psychiatry: I Advances in Quantitative and Molecular Genetics

Advances in quantitative psychiatric genetics as a whole are reviewed with respect to conceptual and methodological issues in relation to statistical model fitting, new genetic designs, twin and adoptee studies, definition of the phenotype, pervasiveness of genetic influences, pervasiveness of environmental influences, shared and nonshared environmental effects, and nature-nurture interplay. Advances in molecular genetics are discussed in relation to the shifts in research strategies to investigate multifactorial disorders (affected relative linkage designs, association strategies, and quantitative trait loci studies); new techniques and identified genetic mechanisms (expansion of trinucleotide repeats, genomic imprinting, mitochondrial DNA, fluorescent in-situ hybridisation, behavioural phenotypes, and animal models); and the successful localisation of genes.

DAMAGE AND REPAIR OF NERVE CELL DNA IN TOXIC STRESS*

It is generally agreed that ALS/PDC is triggered by a disappearing environmental factor peculiar to the lifestyle of people of the western Pacific (i.e., Guam, Irian Jaya, Indonesia, and the Kii Peninsula of Japan). A strong candidate is the cycad plant genotoxin cycasin, the beta-D-glucoside of methylazoxymethanol (MAM). We propose that prenatal or postnatal exposure to low levels of cycasin/MAM may damage neuronal DNA, compromise DNA repair, perturb neuronal gene expression, and irreversibly alter cell function to precipitate a slowly evolving disease ("slow-toxin" hypothesis). In support of our hypothesis, we have demonstrated the following: 1. DNA from postmitotic rodent central nervous system neurons is particularly sensitive to damage by MAM. 2. MAM reduces DNA repair in human and rodent neurons, whereas DNA-repair inhibitors potentiate MAM-induced DNA damage and toxicity in mature rodent nervous tissue. 3. Human neurons (SY5Y neuroblastoma) that are deficient in DNA repair are susceptible to MAM-induced cytotoxicity and DNA damage, whereas overexpression of DNA repair in similar cells is protective. 4. MAM alters gene expression in SY5Y human neuroblastoma cells and, in the presence of DNA damage and reduced DNA repair, enhances glutamate-modulated expression of tau mRNA in rat primary neurons; the corresponding protein (TAU) is elevated in ALS/PDC and Alzheimer's disease. These findings support a direct relationship between MAM-induced DNA damage and neurotoxicity and suggest the genotoxin may operate in a similar manner in vivo. More broadly, a combination of genotoxin-induced DNA damage (via exogenous and/or endogenous agents) and disturbed DNA repair may be important contributing factors in the slow and progressive degeneration of neurons that is characteristic of sporadic neurodegenerative disease. Preliminary studies demonstrate that DNA repair is reduced in the brain of subjects with western Pacific ALS/PDC, ALS, and Alzheimer's disease, which would increase the susceptibility of brain tissue to DNA damage by endogenous/exogenous genotoxins. Interindividual differences in the extent of prior exposure to DNA-damaging agents and/or the efficiency of its repair might produce population variety in the rate of damage accumulation and explain the susceptibility of certain individuals to sporadic neurodegenerative disease. Studies are underway using DNA-repair proficient and deficient neuronal cell cultures and mutant mice to explore gene-environment interplay with respect to MAM treatment, DNA damage, and DNA repair, and the age-related appearance of neurobehavioral and neuropathological compromise.

Opportunities for psychiatry from genetic findings.

The opportunities for psychiatry deriving from available or likely genetic advances are reviewed. Clinical implications are considered in the context of both the misconceptions and benefits associated with relevant genetic findings. Misconceptions include that: heritability estimates have a 'true' fixed value; a high heritability means that environmental interventions will be ineffective; a high heritability within groups means that differences between groups will also be due to genes; genetic effects are determinative; 'genetic' means single abnormal genes; genes associated with disease must be bad and justify eugenic measures; gene therapy will be widely applicable; and genetic screening of the general population will be useful. The benefits include demonstrations that: both genes and environment have an ubiquitous influence; some prevailing diagnostic assumptions are mistaken; genes influence development; the effects of nature and nurture are not separate; and environmental effects tend to be person-specific. The potential value of molecular genetics lies in elucidation of causal processes as they apply to both brain systems and nature-nurture interplay; improving diagnosis and genetic counselling; and the development of improved pharmacological interventions. Advances in genetics will make a major impact on clinical psychiatry, and should bring practical benefits for both prevention and treatment.

Parenting: a genetic-epidemiologic perspective.

To understand the relation between parenting and later psychopathology, it is important to clarify the role of genetic and environmental factors in both the elicitation and the provision of parenting behavior. A 16-item version of the Parental Bonding Instrument was administered to 1) 606 fathers and 848 mothers of an epidemiologic sample of adult female-female twin pairs, who reported on their parenting of their twins; 2) the twins (both members of 546 monozygotic and 390 dizygotic pairs), who reported on the parenting they had received from their father and mother; 3) co-twins from these pairs, who reported on the parenting provided by their father and mother to their twin sister; and 4) members of the adult twin pairs (145 monozygotic and 117 dizygotic) who both had children, who reported on the parenting they provided to their offspring. The data were subjected to model fitting decomposing three sources of variance: additive genetic factors; family, or common, environment; and an individual's unique environment. Responses to the Parental Bonding Instrument produced three factors: parental warmth, protectiveness, and authoritarianism. According to parents, these factors were largely a common environmental experience for their children. Responses from twins, however, indicated that genetic factors played a substantial role in the elicitation of warmth from parents and a more modest role in influencing parental protectiveness and authoritarianism. While reports of twins and co-twins on protectiveness and authoritarianism yielded similar results, analysis of responses from co-twins indicated a degree of importance of genetic factors in eliciting parental warmth which was midway between that from parents' reports and twins' reports. Answers from twins as parents indicated that provision of warmth was substantially heritable, while resemblance between twins in providing protectiveness and authoritarianism was due to family environment. The provision of parenting is influenced by attitudes derived from the parent's family of origin as well as by genetically influenced parental temperamental characteristics. The elicitation of parenting is influenced by temperamental traits of the offspring that are, in turn, under partial genetic control. Genetic factors in both parent and child are more important for warmth than for protectiveness or authoritarianism.

Ethnic differences in drug metabolism.

Interethnic differences in drug-metabolising capacity may be substantial, and they are sufficiently frequent to warrant attention. Such differences may consist of different mean values of quantitative traits in separate populations, or of different frequency distributions as produced by the occurrence of genetic enzyme variants. The collection of population data requires the investigation of substantial numbers of subjects. This may be no problem if drug-metabolising enzymes occur in blood or are sufficiently stable in their tissues to allow investigation in vitro. However, if investigations require the use of probe drugs, new efforts are needed to adapt pharmacokinetic methods to make them suitable for population studies. This development of methods is further called for because genetic variants seem to be more easily detected through the assessment of particular metabolites than through the determination of pharmacokinetic parameters of the parent drug. Many studies with probe drugs comparing different populations have given results that are equivocal in terms of the nature-nurture interplay. However, a set of data with antipyrine has pointed to environmental factors as the principal determinant of differences in metabolising capacity, while data with debrisoquine have indicated monogenically controlled variation of one facet of the cytochrome P-450 system. In several instances, statistically significant differences between population means have been established by testing small numbers of subjects, numbers insufficient to establish distribution patterns that would allow the recognition of genetic polymorphism. The populations studied range from Greenlanders to South African Blacks, but most comparisons pertain to Caucasians and Orientals.