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AbstractDetermining (1) the direction of causation and (2) the size of causal effects between two constructs is a central challenge of the scientific study of humans. In the early 1990s, researchers in behavioral genetics invented what was termed the direction of causation (DoC) model to address exactly these two concerns. The model claims that for any two traits whose mode of inheritance is sufficiently different, the direction of causation can be ascertained using a sufficiently large genetically informative sample. Using a series of simulation studies, we demonstrate a major challenge to the DoC model, namely that it is extremely sensitive to even tiny amounts of non-shared confounding. Even under ideal conditions for the DoC model (a large sample,N= 10,000), a large causal relationship (e.g., a causal correlation of .50) with very different modes of inheritance between the two traits (e.g., a pure AE model for one trait and a pure CE model for another trait) and a modest degree (correlation of .10) of non-shared confounding between the two traits results in the choice of the wrong causal models and estimating the wrong causal effects.

Aim: The present study aims to estimate the relative importance of genetic and environmental factors for health-related quality of life (HRQL) measured by the 12-item Short-Form Health Survey (SF-12). Methods: The study was based on two Danish twin cohorts (46,417 twin individuals) originating from the nationwide, population-based Danish Twin Registry. The twins were approached by a mailed-out questionnaire in 2002. The questionnaire included the SF-12, information on demographic factors, and questions on a variety of specific diseases. Heritability of the SF-12 includes the physical component summary (PCS) and the mental component summary (MCS); and etiologically important variance components were estimated using multivariate biometric models. The respondents were stratified into six groups, based on age and sex. Results: A total of 33,794 (73%) individual twins responded to the survey. The SF-12 was completed by 29,619 individuals, which included 9,120 complete twin pairs. Overall, the best-fitting model explaining the variance of HRQL was the ACE model. The estimated heritability of the SF-12 was between 11% and 35%, whereas between 65% and 89% could be explained by unique environmental or stochastic factors in the different sex and age groups. The highest heritability was seen among older twins. In addition, the genetic correlation between MCS and PCS scores was low (0.07 and 0.23 for males and females, respectively) among younger and high (0.26 and 0.45 for males and females, respectively) in the oldest age group. Both the largest genetic influence on HRQL and the largest genetic overlap between the scores were seen in the oldest age group, which consisted of twins older than 55. The unique environmental correlation between MCS and PCS were generally negative. Conclusion: The heritability of HRQL differs between different age groups. In general, most of the variance in the SF-12 summary components was determined by unique environmental factors.

It is well known that human behavior and individual psychological traits are moderately to substantially heritable. Over the past decade, an increasing number of studies have explored the genetic and environmental influence on religiousness. These studies originate predominantly from countries generally considered more religious than the very secular northern European countries. Comparisons of the results are complicated by diverse definitions of religiousness, but several studies indicate that the influence of the family environment is most predominant in early life, whereas genetic influences increase with age. We performed a population-based twin study of religiousness in a secular society using data from a Web-based survey sent to 6,707 Danish twins born 1970–1989, who were identified in the Danish Twin Registry. We applied Fishman's three conceptual dimensions of religiousness: cognition, practice, and importance. In all polygenic models and biometric analyses, we controlled for gender and age. The study sample comprised 2,237 same sex twins, a response rate of 45%. We found high correlations within both monozygotic and dizygotic twin pairs in most items of religiousness, indicating a large influence from shared environmental factors. Personal religiousness such as praying to God, believing in God, and finding strength and comfort in religion were more influenced by genetic factors than were social forms of religiousness such as church attendance. We found a small tendency for increasing genetic influence with increasing age for some religious items, but not for all.

In this article, we examine the nature of the relationship between educational attainment and ideology. Some scholars have argued that the effect of education on political variables like ideology is inflated due to unaccounted-for family factors, such as genetic predispositions and parental socialization. Using the discordant twin design and data from a large sample of Danish twins, we find that after accounting for confounders rooted in the family, education has a (quasi)-causal effect on economic ideology, but not social ideology. We also examine whether the relationship between education and economic ideology is moderated by levels of economic hardship in the local context where individuals reside. We find that the (quasi)-causal effect of education on economic ideology increases in economically challenged areas.

Systolic and diastolic blood pressure, pulse pressure (PP), and body mass index (BMI) are heritable traits in human metabolic health but their common genetic and environmental backgrounds are not well investigated. The aim of this article was to explore the phenotypic and genetic associations among PP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. The studied sample contained 615 twin pairs (17–84 years) collected in the Qingdao municipality. Univariate and multivariate structural equation models were fitted for assessing the genetic and environmental contributions. The AE model combining additive genetic (A) and unique environmental (E) factors produced the best fit for each four phenotypes. Heritability estimated in univariate analysis ranged from 0.42 to 0.74 with the highest for BMI (95% CI 0.70–0.78), and the lowest for PP (95% CI 0.34–0.49). The multivariate model estimated (1) high genetic correlations for DBP with SBP (0.87), PP with SBP (0.75); (2) low–moderate genetic correlations between PP and DBP (0.32), each BP component and BMI (0.24–0.37); (3) moderate unique environmental correlation for PP with SBP (0.68) and SBP with DBP (0.63); (4) there was no significant unique environmental correlation between PP and BMI. Overall, our multivariate analyses revealed common genetic and environmental backgrounds for PP, BP, and BMI in Chinese twins.

We analyzed the association between mean height and old age cognition in two Nordic twin cohorts with different childhood living conditions. The cognitive performance of 4720 twin individuals from Denmark (mean age 81.6 years, SD = 4.59) and Finland (mean age 74.4 years, SD = 5.26) was measured using validated cognitive screens. Taller height was associated with better cognitive performance in Finland (β-estimates 0.18 SD/10cm, p value < .001, for men and 0.13 SD, p = .008, for women), but this association was not significant in Denmark (β-estimates 0.0093 SD, p value = .16, for men and 0.0075 SD, p value = .016, for women) when adjusted for age and education/social class. Among Finnish participants higher variability of cognitive performance within shorter height quintiles was observed. Analysis using gene-environment interaction models showed that environmental factors exerted a greater impact on cognitive performance in shorter participants, whereas in taller participants' it was explained mainly by genetic factors. Our results suggest that shorter participants with childhood adversity are more vulnerable to environmental risk factors for cognitive impairment.

AbstractNordic twin studies have played a critical role in understanding cancer etiology and elucidating the nature of familial effects on site-specific cancers. The NorTwinCan consortium is a collaborative effort that capitalizes on unique research advantages made possible through the Nordic system of registries. It was constructed by linking the population-based twin registries of Denmark, Finland, Norway and Sweden to their country-specific national cancer and cause-of-death registries. These linkages enable the twins to be followed many decades for cancer incidence and mortality. To date, two major linkages have been conducted: NorTwinCan I in 2011–2012 and NorTwinCan II in 2018. Overall, there are 315,413 eligible twins, 57,236 incident cancer cases and 58 years of follow-up, on average. In the initial phases of our work, NorTwinCan established the world's most comprehensive twin database for studying cancer, developed novel analytical approaches tailored to address specific research considerations within the context of the Nordic data and leveraged these models and data in research publications that provide the most accurate estimates of heritability and familial risk of cancers reported in the literature to date. Our findings indicate an excess familial risk for nearly all cancers and demonstrate that the incidence of cancer among twins mirrors the rate in the general population. They also revealed that twin concordance for cancer most often manifests across, rather than within, cancer sites, and we are currently focusing on the analysis of these cross-cancer associations.

AbstractThe Nordic countries have comprehensive, population-based health and medical registries linkable on individually unique personal identity codes, enabling complete long-term follow-up. The aims of this study were to describe the NorTwinCan cohort established in 2010 and assess whether the cancer mortality and incidence rates among Nordic twins are similar to those in the general population. We analyzed approximately 260,000 same-sexed twins in the nationwide twin registers in Denmark, Finland, Norway and Sweden. Cancer incidence was determined using follow-up through the national cancer registries. We estimated standardized incidence (SIR) and mortality (SMR) ratios with 95% confidence intervals (CI) across country, age, period, follow-up time, sex and zygosity. More than 30,000 malignant neoplasms have occurred among the twins through 2010. Mortality rates among twins were slightly lower than in the general population (SMR 0.96; CI 95% [0.95, 0.97]), but this depends on information about zygosity. Twins have slightly lower cancer incidence rates than the general population, with SIRs of 0.97 (95% CI [0.96, 0.99]) in men and 0.96 (95% CI [0.94, 0.97]) in women. Testicular cancer occurs more often among male twins than singletons (SIR 1.15; 95% CI [1.02, 1.30]), while cancers of the kidney (SIR 0.82; 95% CI [0.76, 0.89]), lung (SIR 0.89; 95% CI [0.85, 0.92]) and colon (SIR 0.90; 95% CI [0.87, 0.94]) occur less often in twins than in the background population. Our findings indicate that the risk of cancer among twins is so similar to the general population that cancer risk factors and estimates of heritability derived from the Nordic twin registers are generalizable to the background populations.

BACKGROUND: In 2014 the Danish Government introduced a wide-ranging school reform that applies to all public schools in Denmark. The reform involves changes in several aspects of the school structure and content. In a physical activity promotion perspective, a distinctive feature of the school reform is that it has become mandatory to integrate an average of 45 min of daily physical activity in the regular school day. The overarching objective of the PHASAR study is to evaluate the implementation and effect of this ambitious policy-driven physical activity promotion initiative on physical activity and overweight. This paper describes in detail the study protocol. METHODS: The evaluation is divided into a quantitative effect evaluation and a combined quantitative and qualitative process evaluation. A total of 31 schools are enrolled in the PHASAR study including more than 2,000 school-aged children. Objectively measured physical activity data are obtained in the PHASAR study in 2017/18 and compared to repeated cross sectional data collected in four historical school-based studies from 1998 to 2012. Body mass index data from 2012 to 2018 will be collected from The Child Database, which includes repeated cross-sectional assessments on approximately 100,000 children annually. In the absence of a control group, interrupted time-series analysis will be used to evaluate pre- and post-reform physical activity and body mass index levels and trends. A characterization of the school environment for physical activity promotion on a political, environmental, organizational and individual level and school implementation processes will be conducted to evaluate the implementation process. Data will be collected using interviews, surveys, document analyses and observations. DISCUSSION: The PHASAR study is a rare opportunity to evaluate the effectiveness of a nation-wide policy-driven school-based physical activity promotion initiative. The use of objectively measured pre- and post-reform physical activity and body mass index data combined with a characterization of the school implementation processes for physical activity promotion will provide a comprehensive source to evaluate the school reform. The study findings have the potential to influence national and international policy makers, health professionals and school staff.

BACKGROUND: In 2014 the Danish Government introduced a wide-ranging school reform that applies to all public schools in Denmark. The reform involves changes in several aspects of the school structure and content. In a physical activity promotion perspective, a distinctive feature of the school reform is that it has become mandatory to integrate an average of 45 min of daily physical activity in the regular school day. The overarching objective of the PHASAR study is to evaluate the implementation and effect of this ambitious policy-driven physical activity promotion initiative on physical activity and overweight. This paper describes in detail the study protocol. METHODS: The evaluation is divided into a quantitative effect evaluation and a combined quantitative and qualitative process evaluation. A total of 31 schools are enrolled in the PHASAR study including more than 2,000 school-aged children. Objectively measured physical activity data are obtained in the PHASAR study in 2017/18 and compared to repeated cross sectional data collected in four historical school-based studies from 1998 to 2012. Body mass index data from 2012 to 2018 will be collected from The Child Database, which includes repeated cross-sectional assessments on approximately 100,000 children annually. In the absence of a control group, interrupted time-series analysis will be used to evaluate pre- and post-reform physical activity and body mass index levels and trends. A characterization of the school environment for physical activity promotion on a political, environmental, organizational and individual level and school implementation processes will be conducted to evaluate the implementation process. Data will be collected using interviews, surveys, document analyses and observations. DISCUSSION: The PHASAR study is a rare opportunity to evaluate the effectiveness of a nation-wide policy-driven school-based physical activity promotion initiative. The use of objectively measured pre- and post-reform physical activity and body mass index data combined with a characterization of the school implementation processes for physical activity promotion will provide a comprehensive source to evaluate the school reform. The study findings have the potential to influence national and international policy makers, health professionals and school staff.

AbstractThe Danish Twin Registry (DTR) was established in the 1950s, when twins born from 1870 to 1910 were ascertained, and has since been extended to include twins from birth cohorts until 2009. The DTR currently comprises of more than 175,000 twins from the 140 birth cohorts. This makes the DTR the oldest nationwide twin register and among the largest in the world. The combination of data from several surveys, including biological samples and repeated measurements on the same individuals, and data from Danish national registers provides a unique resource for a wide range of twin studies. This article provides an updated overview of the data in the DTR: First, we provide a summary of the establishment of the register, the different ascertainment methods and the twins included; then follows an overview of major surveys conducted in the DTR since 1994 and a description of the DTR biobank, including a description of the molecular data created so far; finally, a short description is given of the linkage to Danish national registers at Statistics Denmark and some recent examples of studies using the various data resources in the DTR are highlighted.

The genetic influences on aging-related phenotypes, including cognition and depression, have been well confirmed in the Western populations. We performed the first twin-based analysis on cognitive performance, memory and depression status in middle-aged and elderly Chinese twins, representing the world's largest and most rapidly aging population. The sample consisted of 384 twin pairs with a median age of 50 years. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) scale; memory was assessed using the revised Wechsler Adult Intelligence scale; depression symptomatology was evaluated by the self-reported 30-item Geriatric Depression (GDS-30)scale. Both univariate and multivariate twin models were fitted to the three phenotypes with full and nested models and compared to select the best fitting models. Univariate analysis showed moderate-to-high genetic influences with heritability 0.44 for cognition and 0.56 for memory. Multivariate analysis by the reduced Cholesky model estimated significant genetic (rG= 0.69) and unique environmental (rE= 0.25) correlation between cognitive ability and memory. The model also estimated weak but significant inverse genetic correlation for depression with cognition (-0.31) and memory (-0.28). No significant unique environmental correlation was found for depression with other two phenotypes. In conclusion, there can be a common genetic architecture for cognitive ability and memory that weakly correlates with depression symptomatology, but in the opposite direction.