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One of Irving I. Gottesman's many contributions to behavior genetics, and part of his enduring legacy, was his introduction of the term 'endophenotype' to the field of psychiatry. Gottesman argued that focusing on endophenotypes, rather than complex heterogeneous clinical diagnoses, could help elucidate disease etiology. Although a different strategy for gene identification ultimately proved successful (that of amassing extremely large sample sizes in order to overcome the 'noise' of heterogeneity and have sufficient power to find genes of very small effect), the endophenotype concept continues to make a meaningful contribution to the field. The endophenotype concept forced the field to move beyond a simple disease model of finding genes 'for' psychiatric outcomes, and reminded us that genes are quite distal from complex behavioral outcomes and disorders. Endophenotypes called our attention to the steps along that pathway. In that process, the concept of endophenotypes evolved and expanded to include discussion of the role that other intermediary traits and psychological processes play in the development and genetic etiology of psychiatric and substance use disorders. As large-scale consortia continues to identify genes and generate genome-wide polygenic scores that are associated with behavioral outcomes, the next important step will be to characterize the pathways and mechanisms by which genetic risk unfolds. This essential step of mapping risk from genes to behavior is an evolution that follows naturally from the endophenotype concept, and could ultimately translate into improved prevention and intervention for individuals who are pre-disposed to mental health challenges.

Aim: In this study, we introduce the first twin study in Turkey, focusing on smoking behavior, and laying the foundation to register all twins born in Turkey for research purposes. Using Turkish twins will contribute to our understanding of health problems in the context of cultural differences. Materials and methods: We assessed 309 twin pairs (339 males and 279 females) aged between 15 and 45 years living in the Kırıkkale and Ankara regions of Turkey, and administered a health and lifestyle interview that included questions about smoking status and smoking history. We analyzed the data using descriptive statistics, t-tests, chi-square tests, and bivariate and multivariate clustered logistic regression. In addition, we fit bivariate Structural Equation Models (SEM) to determine contributions of latent genetic and environmental factors to smoking outcomes in this sample. Results: One hundred seventy-eight participants (28.8%) were identified as smokers, smoking every day for a month or longer, of whom 79.2% were males and 20.8% were females. Mean values for number of cigarettes per day and the Fagerstrom Test of Nicotine Dependence (FTND; Fagerstrom, 1978) score were higher in males than in females, and age of onset was earlier in males. There was a significant positive correlation between the FTND score and number of cigarettes smoked per day, and a significant negative correlation between both variables and age at onset of smoking. Our study showed that gender, presence of a smoking twin in the family, age, alcohol use, marital status, daily sports activities, and feeling moody all played a significant role in smoking behavior among twins. The twin analysis suggested that 79.5% of the liability to FTND was influenced by genetic factors and 20.5% by unique environment, while familial resemblance for smoking initiation was best explained by common environmental factors. Conclusions: Marked differences in the prevalence of smoking behavior in men versus women were observed for the Turkish population. Genetic analyses showed that common environmental factors primarily contributed to smoking initiation, while genetic factors explained a greater proportion of variance in liability to nicotine dependence. Our study shows higher heritability estimate of the FTND scores and higher shared environmental influence on smoking initiation for both males and females than reported in previous studies.

AbstractThe National Academy of Sciences — National Research Council (NAS-NRC) twin panel, created nearly 50 years ago, had twin zygosity determined primarily via a similarity questionnaire that has been estimated to correctly classify at least 95% of twins. In the course of a study on the genetics of healthy ageing in the NAS-NRC twins, DNA was collected for genome-wide scanning and zygosity confirmation was examined in 343 participating pairs. The sample was supplemented from two other studies using NAS-NRC twins where one or both co-twins were suspected to have Alzheimer disease or another dementia, or Parkinson's disease. Overall 578 twin pairs with DNA were analyzed. Zygosity assignment for 96.8% (519/536) was confirmed via questionnaire. Among 42 pairs whose questionnaire responses were inconclusive for assigning zygosity, 50% were found to be monozygous (MZ) and 50% were dizygous (DZ). There was some evidence for greater misclassification of presumed DZ pairs in the healthy ageing study where participation favored pairs who were similar in having a favorable health history and willingness to volunteer without any element of perceived risk for a specific disease influencing participation.

In order to further understand why depressive symptoms are associated with negative goal appraisals, the present study examined the genetic and environmental correlations and interactions between depressive symptoms and career-related goal appraisals. A total of 1,240 Finnish twins aged 21–26 years completed a questionnaire containing items on the appraisal of their career goals along five dimensions: importance, progress, effort, strain, and self-efficacy. In the same questionnaire, the 10-item General Behavior Inventory assessed depressive symptoms. Structural equation modeling was used to evaluate the genetic and environmental correlations and gene–environment interactions between the career-goal appraisals and depressive symptoms. Associations were identified, and were attributed to environmental factors. Of the career-related goal appraisals, the shared environmental component was of a higher magnitude for the dimension of strain among the depressed compared with non-depressed subjects. The results indicate that the interplay between depressive symptoms and negative career-related goal appraisals is significantly affected by environmental factors, and thus possibly susceptible to targeted interventions.

We examined whether externalizing problem behaviors (hyperactivity–impulsivity, aggressiveness, and inattention) predict illicit drug use independently, or whether their associations with drug use are mediated through cigarette smoking. We used a prospective longitudinal design within theFinnTwin12-17study among Finnish adolescents with baseline at age 12 and follow-up surveys at ages 14 and 17. Path models were conducted withMplusand included 1992 boys and 2123 girls. The outcome was self-reported ever use of cannabis or other illicit drugs at age 17. The predictors were: externalizing behaviors (hyperactivity–impulsivity, aggressiveness, and inattention) assessed by teachers and parents (age 12) and self-reported cigarette smoking (age 14). The findings differed across behavior studied. The association of hyperactivity–impulsivity with drug use was mostly mediated through earlier cigarette smoking. Concerning aggressiveness and inattention, the results were different among girls than boys. Among girls no significant mediation occurred, whereas among boys more consistent evidence on mediation was seen. Consistently in all models, the direct association of early cigarette smoking on drug use was strong and highly significant. We conclude that the associations of externalizing problem behaviors with illicit drug use are partially mediated through cigarette smoking. Although interventions targeting externalizing problem behaviors may protect adolescents from early onset smoking and subsequently experimenting with drugs, interventions to prevent cigarette smoking initiation are also important in reducing risk of later drug use.

AbstractIn contrast to many phenotypes that have been studied using twin designs, substance use shows considerable evidence of environmental influence. Accordingly, specifying the relevant environments and understanding the nature of their effects is an important research priority. Twin studies also have demonstrated that the importance of genetic and environmental influences varies across development for a variety of behavioral outcomes, including substance use. Here, we report analyses exploring moderating effects associated with parenting and peer characteristics on adolescent smoking and drinking, measured at ages 14 and 17. We find significant evidence of moderating effects associated with two dimensions of parenting (parental monitoring and time spent in activities with parents) on adolescent smoking, measured at two time points across development, but no moderating effects on adolescent drinking. Genetic influences on smoking increased, and common environmental effects decreased, as adolescents reported less parental monitoring and spending more time with their parents. Conversely, we find evidence that adolescent drinking is more strongly influenced by peer characteristics. The importance of genetic predispositions was increased among adolescents who reported more friends who used alcohol. These analyses illustrate the importance of incorporating measured aspects of the environment into genetically informative twin models to begin to understand how specific environments are related to various outcomes. Furthermore, they illustrate the importance of using a developmental perspective to understand how specific influences may vary across different ages, and across different phenotypes.