Review. Genetics of addictions: strategies for addressing heterogeneity and polygenicity of substance use disorders

Addictions are common psychiatric disorders that exert high cost to the individual and to society. Addictions are a result of the interplay of multiple genetic and environmental factors. They are characterized by phenotypic and genetic heterogeneity as well as polygenicity, implying a contribution of different neurobiological mechanisms to the clinical diagnosis. Therefore, treatments for most substance use disorders are often only partially effective, with a substantial proportion of patients failing to respond. To address heterogeneity and polygenicity, strategies have been developed to identify more homogeneous subgroups of patients and to characterize genes contributing to their phenotype. These include genetic linkage and association studies as well as functional genetic analysis using endophenotypes and animal behavioural experimentation. Applying these strategies in a translational context aims at improving therapeutic response by the identification of subgroups of addiction patients for individualized, targeted treatment strategies. This article aims to discuss strategies addressing heterogeneity and polygenicity of substance use disorders by presenting results of recent research on genetic and environmental components of addiction. It will also introduce the European IMAGEN study that aims to integrate methodical approaches discussed in order to identify the genetic and neurobiological basis of behavioural traits relevant to the development of addictions.     

Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy

ABSTRACT: Genetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environments. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae. In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis.     

Genetic and environmental influences on expression of recurrent headache as a function of the reporting age in twins.

To explore age-related mechanisms in the expression of recurrent headache, we evaluated whether genetic and environmental influences are a function of the reporting age using questionnaire information that was gathered in 1973 for 15- to 47-year-old Swedish twins (n = 12,606 twin pairs). Liability to mixed headache (mild migraine and tension-type headache) was explained by non-additive genetic influences (49%) in men aged from 15 to 30 years and additive genetic plus shared environmental influences (28%) in men aged from 31 to 47 years. In women, the explained proportion of variance, which was mainly due to additive genetic effects, ranged from 61% in adolescent twins to 12% in twins aged from 41 to 47 years, whereas individual specific environmental variance was significantly lower in twins aged from 15 to 20 years than in twins aged from 21 to 30 years. Liability to migrainous headache (more severe migraine) was explained by non-additive genetic influences in men, 32% in young men and 45% in old men, while total phenotypic variance was significantly lower in young men than in old men. In women, the explained proportion of variance ranged from 91% in the youngest age group to 37% in the oldest age group, with major contributions from non-additive effects in young and old women (15-20 years and 41-47 years, respectively) and additive genetic effects in intermediate age groups (21-40 years). While total variance showed a positive age trend, genetic variance tended to be stable across age groups, whereas individual specific environmental variance was significantly lower in adolescent women as compared to older women.     

GENETIC ANALYSIS OF MORNINGNESS AND EVENINGNESS

We studied the influence of genetic factors on individual differences in morningness-eveningness in a sample of Dutch twin families. Data were collected from adolescent twins (mean age 17.8 yr) and their parents (mean age of fathers 48.0 yr and of mothers 46.0 yr) and a sample of older twins (mean age 46.5 yr). Scores on morningness-eveningness were rated on a 5-point scale. Parents were more morning oriented than their children, and women were more morning oriented than men. With a twin-family study, separation of genetic and environmental influences on variation in morningness-eveningness is possible. Including parents and older twins in the study makes it possible to explore generation differences in these effects. The correlation between monozygotic twins was more than twice the correlation between dizygotic twins. This indicates that genetic effects may not operate in an additive manner. Therefore, a model that included genetic dominance was explored. Biometrical model fitting showed no sex differences for the magnitude of genetic and environmental factors. The total heritability—the sum of additive and nonadditive genetic influences—for morningness-eveningness was 44% for the younger generation and 47% for the older generation. However, the genetic correlation between the generations turned out to be lower than 0.5, suggesting that different genes for morningness-eveningness are expressed in both generations. (Chronobiology International, 18(5), 809–822, 2001)     

GENETIC ANALYSIS OF MORNINGNESS AND EVENINGNESS

We studied the influence of genetic factors on individual differences in morningness-eveningness in a sample of Dutch twin families. Data were collected from adolescent twins (mean age 17.8 yr) and their parents (mean age of fathers 48.0 yr and of mothers 46.0 yr) and a sample of older twins (mean age 46.5 yr). Scores on morningness-eveningness were rated on a 5-point scale. Parents were more morning oriented than their children, and women were more morning oriented than men. With a twin-family study, separation of genetic and environmental influences on variation in morningness-eveningness is possible. Including parents and older twins in the study makes it possible to explore generation differences in these effects. The correlation between monozygotic twins was more than twice the correlation between dizygotic twins. This indicates that genetic effects may not operate in an additive manner. Therefore, a model that included genetic dominance was explored. Biometrical model fitting showed no sex differences for the magnitude of genetic and environmental factors. The total heritability—the sum of additive and nonadditive genetic influences—for morningness-eveningness was 44% for the younger generation and 47% for the older generation. However, the genetic correlation between the generations turned out to be lower than 0.5, suggesting that different genes for morningness-eveningness are expressed in both generations. (Chronobiology International, 18(5), 809-822, 2001)     

Genetic and environmental factors in complex diseases: the older Finnish Twin Cohort.

In studies on the Finnish Twin Cohort, we investigate genetic and environmental determinants of common, complex diseases, and their behavioral risk factors in Finland, a genetically unique and culturally homogenous population. We have formed the following databases: 1) Like-sexed twin pairs (13,888 pairs of known zygosity) form the older Twin Cohort. They have participated since 1975 in mail surveys, in clinical examinations for subsamples, and have been followed-up for morbidity using national medical registers; 2) The older Twin Cohort was expanded in 1996 to include opposite-sex pairs born 1938-1957 (c. 8000 pairs); 3) Two, new longitudinal studies of adolescent twins and their families, form a complementary, ongoing study base described in more detail in an accompanying article. Genetic and environmental effects vary over the life-span, and only longitudinal studies in genetically informative data sets permits the evaluation of such effects. Finally, the inclusion of DNA-based genetic information in a phenotypically rich family data base will offer a unique resource for research in genetic epidemiology and behavioral medicine.     

Investigating the genetic and environmental structure of Cloninger's personality dimensions in adolescence.

In this study we examined the genetic and environmental structure of four dimensions from Cloninger's personality system: novelty-seeking (NS), harm-avoidance (HA), reward-dependence (RD), and persistence (PS). Although adult twin studies suggest that these personality dimensions are moderately heritable, this is the first twin study of Cloninger's personality dimensions in adolescence--a period marked by significant physiological and social changes. Study participants included 1851 adolescent twins between the ages of 11 and 18 years; 878 complete twin pairs and 95 singleton-responding twins. Subjects were participants in two community-based samples of twins residing in the state of Colorado. Results indicated that cross-sectional mean levels for NS, HA and RD tended to show modest increases across the adolescent years, while PS showed modest mean decreases. Consistent sex differences in means were found only for RD. Univariate biometrical twin models were used to decompose trait variance into genetic and environmental sources. Results indicated that for NS, HA and RD additive genetic influences and unique environmental effects were sufficient to explain the data. PS, however, could be explained by unique and common environmental effects only, with different patterns of common environmental effects for males and females. We found moderate heritability estimates for NS, HA and RD ranging from .28 to .36--with no evidence for sex-limitation in those influences.     

HPA-axis activity in alcoholism: examples for a gene-environment interaction.

Genetic and environmental influences are both known to be causal factors in the development and maintenance of substance abuse disorders. This review aims to focus on the contributions of genetic and environmental research to the understanding of alcoholism and how gene-environment interactions result in a variety of addiction phenotypes. Gene-environment interactions have been reviewed by focusing on one of the most relevant environmental risk factors for alcoholism, stress. This is examined in more detail by reviewing the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and its genetic and molecular components in this disorder. Recent evidence from animal and human studies have shown that the effects of stress on alcohol drinking are mediated by core HPA axis genes and are associated with genetic variations in those genes. The findings of the studies discussed here suggest that the collaborations of neuroscience, psychobiology and molecular genetics provide a promising framework to elucidate the exact mechanisms of gene-environment interactions as seen to convene upon the HPA axis and effect phenotypes of addiction.     

Genetic and environmental influences on self-esteem in a Japanese twin sample.

The purpose of the present study is to clarify the mechanism of Japanese self-esteem (SE) in genetic and environmental influences using twin methodology. Eighty-one pairs of adolescent twins, including 50 pairs of monozygotic (MZ) twins and 31 pairs of dizygotic (DZ) twins, participated in this study. Self-esteem was assessed using the Rosenberg Self-Esteem Scale (RSES), translated into Japanese. As a result of using univariate twin analyses, model comparisons using the Akaike Information Criterion (AIC) indicated that the AE model was the best fit (AIC = -5.35). In the best-fitting AE model, the heritability (a2) of SE was revealed to be moderate, accounting for 49% of the variance; environmental influences (individual-specific environmental factors) explained 51% of the variance. These results are consistent with the findings of some behavioral genetics studies of SE in the West and show that there is no difference between Western and Japanese populations in the mechanism of SE considering genetic and environmental influences. The results also suggest the importance of considering both genetic and environmental factors in studies of Japanese SE.     

Genetics of GABAergic signaling in nicotine and alcohol dependence

Both nicotine and alcohol addictions are common chronic brain disorders that are of great concern to individuals and society. Although genetics contributes significantly to these disorders, the susceptibility genes and variants underlying them remain largely unknown. Many years of genome-wide linkage and association studies have implicated a number of genes and pathways in the etiology of nicotine and alcohol addictions. In this communication, we focus on current evidence, primarily from human genetic studies, supporting the involvement of genes and variants in the GABAergic signaling system in the etiology of nicotine dependence and alcoholism based on linkage, association, and gene-by-gene interaction studies. Current efforts aim not only to replicate these findings in independent samples, but also to identify which variant contributes to the detected associations and through what molecular mechanisms.     

Twins. Novel uses to study complex traits and genetic diseases

The challenge faced by research into the genetic basis of complex disease is to identify genes of small relative effect against a background of substantial genetic and environmental variation. This has focused interest on a classical epidemiological design: the study of twins. Through their precise matching for age, the common family environment and background environmental variation, studying diseases in non-identical twins provides a means to enhance the power of conventional strategies to detect genetic influence through linkage and association. The unique matching of identical twins provides researchers with ways to isolate the function of individual genes involved in disease together with approaches to understanding how genes and the environment interact.     

Use of the correlation of liability in twins and siblings in the study of birth defects

The epidemiologic approach to determining the etiology of disease involves identification of potential risk factors and then comparison of disease incidence among people with varying levels of exposure to the potential risk factors. This paper defines risk factors which correspond to different levels of genetic and environmental proximity to index cases of birth defects. Genetic proximity is estimated by the coefficient of relationship (R): 0.5 for siblings and dizygotic twins and 1.0 for monozygotic twins. Environmental proximity is measured by a combination of two variables: one variable for those potentially preventable risk factors common to siblings (S) and another for those common only to twins (T). Discordance in identical twins is attributed to a third type of environmental factors (U) that are unshared by twins and include random (stochastic) factors. The association between these risk factors and birth defects is estimated by using a linear model of the correlation of liability for different relatives. The coefficients derived from the model reflect the relative importance of genetic and different types of environmental risk factors as causes for the defects and can be used to identify birth defects most likely to be caused by measurable and possibly preventable risk factors. These defects could then be assigned high priority for future studies and preventive efforts.     

Atopic disease and immunoglobulin E in twins reared apart and together.

Both genetic and environmental influences have been implicated in the etiology of atopic disease and in the determination of serum IgE levels. To quantify the relative contribution of these influences, we studied the prevalence of asthma and seasonal rhinitis, skin-test response, total serum IgE levels, and specific IgE, as measured by RAST, in a sample of MZ and DZ twins reared apart or together. Concordance rates for asthma, rhinitis, positive skin tests, and RAST were calculated. MZ twins, whether reared apart or together, showed a greater concordance than dizygotic twins reared apart or together. Maximum-likelihood tests of genetic and environmental components of the variation of total IgE levels revealed a substantial genetic component and a negligible contribution from common familial environmental effects.     

Magnesium homeostasis: Mechanisms and inherited disorders

Mechanisms of magnesium homeostasis intensively studied over the last 10–15 years by means of pathophysiological and molecular genetic approaches have been considered. Impairments of magnesium homeostasis causes the development of magnesium-deficient states, which have been found in many common diseases (diabetes mellitus, cardiovascular diseases, chronic fatigue syndrome, alcoholism, psychiatric and neurologic diseases, etc.), stress condition, effects of some environmental factors as well as therapy with some drugs. Special attention is paid to familial hypomagnesemias caused by genetic defects of magnesium transport systems. The review considers clinical and biochemical characteristics of twelve familial disorders including mechanisms of their development. Deeper understanding of mechanisms of regulation of magnesium homeostasis will results in the development of new approaches in diagnostics, prophylaxis and treatment of magnesium-deficient conditions.     

Adolescent religiousness and its influence on substance use: preliminary findings from the Mid-Atlantic School Age Twin Study.

Research has consistently shown that religiousness is associated with lower levels of alcohol and drug use, but little is known about the nature of adolescent religiousness or the mechanisms through which it influences problem behavior in this age group. This paper presents preliminary results from the Mid-Atlantic School Age Twin Study, a prospective, population-based study of 6-18-year-old twins and their mothers. Factor analysis of a scale developed to characterize adolescent religiousness, the Religious Attitudes and Practices Inventory (RAPI), revealed three factors: theism, religious/spiritual practices, and peer religiousness. Twin correlations and univariate behavior-genetic models for these factors and a measure of belief that drug use is sinful reveal in 357 twin pairs that common environmental factors significantly influence these traits, but a minor influence of genetic factors could not be discounted. Correlations between the multiple factors of adolescent religiousness and substance use, comorbid problem behavior, mood disorders, and selected risk factors for substance involvement are also presented. Structural equation modeling illustrates that specific religious beliefs about the sinfulness of drugs and level of peer religiousness mediate the relationship between theistic beliefs and religious/spiritual practices on substance use. Limitations and future analyses are discussed.     

Social science methods for twins data: integrating causality, endowments, and heritability

Twins have been extensively used in economics, sociology, and behavioral genetics to investigate the role of genetic endowments on a broad range of social, demographic, and economic outcomes. However, the focus in these literatures has been distinct.: The economic literature has been primarily concerned with the need to control for unobserved endowments--including as an important subset, genetic endowments--in analyses that attempt to establish the impact of one variable, often schooling, on a variety of economic, demographic, and health outcomes. Behavioral genetic analyses have mostly been concerned with decomposing the variation in the outcomes of interest into genetic, shared environmental, and non-shared environmental components, with recent multivariate analyses investigating the contributions of genes and the environment to the correlation and causation between variables. Despite the fact that twins studies and the recognition of the role of endowments are central to both of these literatures, they have mostly evolved independently. In this paper we develop formally the relationship between the economic and behavioral genetic approaches to the analyses of twins, and we develop an integrative approach that combines the identification of causal effects, which dominates the economic literature, with the decomposition of variances and covariances into genetic and environmental factors that are the primary goal of behavioral genetic approaches. We apply this integrative ACE-beta approach to an illustrative investigation of the impact of schooling on several demographic outcomes such as fertility and nuptiality and health.     

Shared aetiology of risky sexual behaviour and adolescent misconduct: genetic and environmental influences

Risky sexual behaviour (RSB) is a major risk factor for serious diseases as well as unplanned pregnancy. It is not known if RSB has a genetic basis or if it is only influenced by social and cultural conditions. Adolescent conduct disorder has previously been linked to RSB and has been found to be influenced by both genetic and environmental factors. In this study, we look at normal variation in a broad measure of RSB and in retrospectively reported adolescent misconduct in a large community sample of twins ( n  = 4904) to partition the variance and covariance between the traits into genetic and environmental components. We found that RSB is influenced to the same extent by genes, shared environment and unshared environment. Adolescent misconduct is moderately influenced by genetic factors and only modestly by shared environmental factors. Moreover, RSB is associated with adolescent misconduct ( r  = 0.5), primarily because of genetic correlation between the variables. The implications of our findings as well as possible sex differences are discussed.     

Body mass index gain, fast food, and physical activity: effects of shared environments over time

Objective : The magnitude of environmental vs. genetic effects on BMI, diet, and physical activity (PA) is widely debated. We followed a sibling cohort (where individuals shared households in childhood and adolescence) to young adulthood (when some continued sharing households and others lived apart) to examine the role of discordant environments in adult twins’ divergent trends in BMI and health behaviors and to quantify the variation in BMI and behavior among all siblings that is attributable to environmental and additive genetic effects. Research Methods and Procedures : In the National Longitudinal Study of Adolescent Health, siblings sharing households for ≥10 years as adolescents (mean age = 16.5 ± 1.7 years; N = 5524) were followed into adulthood (mean = 22.4 ± 1.8 years; N = 4368), self‐reporting PA, sedentary behavior, and dietary characteristics. Adult BMI and adolescent z scores were derived from measured height and weight. Results : Compared with those living together, twins living apart exhibited greater discordance in change in BMI, PA, and fast food intake from adolescence to adulthood. Adolescent household environments accounted for 8% to 10% of variation in adolescent fast food intake and sedentary behaviors and 50% of variation in adolescent overweight. Adolescent household effects on PA were substantially greater in young adulthood (accounting for 50% of variation) vs. adolescence. Young adult fast food intake was significantly affected by young adult household environment, accounting for 12% of variation. Discussion : These findings highlight important environmental influences on BMI, PA, and fast food intake during the transition to adulthood. Household and physical environments play an important role in establishing long‐term behavior patterns.     

Chinese National Twin Registry as a resource for genetic epidemiologic studies of common and complex diseases in China.

Twins, due to their unique genetic and environmental relationships, have provided crucial insight in our understanding of genetic contributions to numerous etiologically complex disorders in developed countries. As the leading cause of death and adult disability, cardio- and cerebrovascular diseases are common in China, followed by cancer. Obesity and psychological disorders are increasing. The overall goal of this program is to develop a resource for genetic epidemiologic studies of these and other common and complex diseases in China. Our initial focus is to delineate the genetic and environmental determinants of vascular diseases in general, coronary artery disease (CAD) and stroke in particular. To date, we have over 4500 twin pairs registered and about 700 twin pairs studied for various metabolic traits (e.g., lipids, glucose, insulin, etc.). The long-term plan of this program is to (1) establish a population-based twin registry from several selected regions in China for future studies of specific common complex diseases; (2) conduct detailed phenotyping for clinical and intermediate traits related to cardiovascular diseases; (3) expand studies of twins to twin families by including their parents, siblings, and offspring for genetic linkage and association studies; and (4) follow up twins in the registry longitudinally. The goals of the program are health education and promotion of healthy behavior, early identification of cases to provide timely medical attention, and the evaluation of long-term effects of identified risk factors. We want to develop collaborations with investigators who have expertise in cancer, psychological disorders, and other disease areas.