Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9–11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9–13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47–0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61–78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.

The Vietnam Era Twin Study of Aging (VETSA) is a large-scale investigation of cognitive aging from middle to later age. The intended sample of 1440 twin subjects is recruited from the Vietnam Era Twin Registry (VETR), a registry of middle-aged male-male twin pairs who both served in the military during the Vietnam conflict (1965–1975). VETSA employs a multitrait multimethod approach to cognitive assessment to focus on the genetic and environmental contributions to cognitive processes over time, as well as the relative contributions to cognitive aging from health, social, personality, and other contextual factors. The cognitive domains of episodic memory, working memory, abstract reasoning, and inhibitory executive functioning are assessed through neuropsychological testing. In addition, VETSA obtains the participant's score on the Armed Forces Qualification Test, taken at the time of induction into the military around age 20 years, and readministers the test. Two other projects — VETSA Cortisol and VETSA Magnetic Resonance Imaging — are also in progress using subsamples of the VETSA twins. Prior waves of data collection by VETSA investigators using the VETR have provided historical data on physical and mental health, while future waves of VETSA data collection are planned every 5 years. These methods will provide data on multiple pheno-types in the same individuals with regard to genetic and environmental contributions to cognitive functioning over time, personality and interpersonal risk and protective factors, stress and cortisol regulation, and structural brain correlates of aging processes.

In 2002 and 2006, review papers have described the Finnish Twin Cohort and studies conducted on these population-based, longitudinal data sets with extensive follow-up data. Three cohorts have been established: the older twin cohort in the 1970s, and the Finntwin12 and Finntwin16 studies initiated in the 1990s. The present review provides on update on the latest data collections conducted since the previous review. These cover the fourth waves of data collection in the older cohort (twins born before 1958) and Finntwin12 (twins born 1983–1987). The fifth wave of data collection in Finntwin16 (twins born 1975–1979) also included assessments of their spouses/partners. An analysis of mortality in the older cohort from 1975 to 2009 indicates that the mortality of adult twins (as individuals) does not differ from the population at large. Based on the cohorts, many sub-studies with more detailed phenotyping and collection of omics data have been conducted or are in progress. We also contribute to numerous national and international collaborations.

In 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.

We examined the contribution of genetic and environmental influences to variation in resting systolic (SBP) and diastolic (DBP) blood pressure in participants from 4 twin studies carried out between 1986 and 2003. A total of 1577 subjects (682 males, 895 females) participated. There were 580 monozygotic twins, 664 dizygotic twins and 333 of their siblings. The 4 studies sampled subjects in different age groups (average age 17, 32, 37, 44 years), allowing for comparison of the relative contribution of genetic and environmental factors across the first part of the life span. Blood pressure was assessed under laboratory conditions in 3 studies and by ambulatory monitoring in 1 study. Univariate analyses of SBP and DBP showed significant heritability of blood pressure in all studies (SBP h2 48% to 60%, DBP h2 34% to 67%). Overall, there was little evidence for sex differences in blood pressure heritability, and no evidence for differences in heritability due to measurement strategy (laboratory vs. ambulatory). For 431 subjects there were data from 2 or more occasions that allowed us to assess the tracking of blood pressure over time and to estimate the genetic and environmental contributions to blood pressure tracking. Correlations over time across an average period of 7.1 years (tracking) were between .41 and .70. Multivariate genetic analyses showed that blood pressure tracking was entirely explained by the same genetic factors being expressed across time. It was concluded that whole genome scans for resting blood pressure can safely pool data from males and females, laboratory and ambulatory recordings, and different age cohorts.

Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.

A requirement for performing robust genetic and statistical analyses on twins is correctly assigned zygosities. In order to increase the power to detect small risk factors of disease, zygosity testing should also be amenable for high throughput screening. In this study we validate and implement the use of a panel of 50 single nucleotide polymorphisms (SNPs) for reliable high throughput zygosity testing and compare it to a panel of 16 short tandem repeats (STRs). We genotyped both genomic (gDNA) and whole genome amplified DNA (WGA DNA), ending up with 47 SNP and 11 STR markers fulfilling our quality criteria. Out of 99 studied twin pairs, 2 were assigned a different zygosity using SNP and STR data as compared to self reported zygosity in a questionnaire. We also performed a sensitivity analysis based on simulated data where we evaluated the effects of genotyping error, shifts in allele frequencies and missing data on the qualitative zygosity assignments. The frequency of false positives was less than 0.01 when assuming a 1% genotyping error, a decrease of 10% of the observed minor allele frequency compared to the actual values and up to 10 missing markers. The SNP markers were also successfully genotyped on both gDNA and WGA DNA from whole blood, saliva and filter paper. In conclusion, we validate a robust panel of 47 highly multiplexed SNPs that provide reliable and high quality data on a range of different DNA templates.

‘Healthy Twin’ is a twin family study extension of the existing Korean Twin-Family Register. Healthy Twin recruits adult like-sex twins over the age of 30 and their adult family members. Healthy Twin protocols are primarily tailored to the study of the quantitative trait loci of complex traits as well as to the role of environment in the etiology of complex diseases. A full-length survey is underway, including questionnaires, health examinations and the collection of biological specimens. So far, 820 individuals (169 twin pairs and their families) have participated in the survey and 1068 individual twins (608 twin pairs) have replied to the mailed zygosity questionnaire as of July 2006. The first phase (2005–2006) of Healthy Twin will recruit 1550 individuals (including about 380 twin pairs), and the second phase a proposed 1500 to 2500 additional participants. We report study protocols and zygosity and the distribution of family size of the study participants.

We compared the results of different methods for diagnosing zygosity in a sample of 237 same-sex pairs of twins assessed at 5 and 18 months of age. Despite the twins' very young age and early stage of development, physical similarity was concordant with genotyping in 91.9% of cases at 5 months and 93.8% of cases at 18 months, for a subsample of 123 and 113 pairs, respectively. This concordance rate was obtained following a case-by-case assessment of each pair's physical similarity using a shortened version of the Zygosity Questionnaire for Young Twins (Goldsmith, 1991). Taking into account the chorionicity data available from the twins' medical files, we were able to classify correctly 96% of the pairs, an accuracy rate comparable to previously reported rates obtained with older twins. Chorionicity data is especially useful since we found that monochorionic MZ twins are more difficult than dichorionic MZ twins to diagnose by physical similarity at these young ages. The relative cost-benefit of methods based on reported physical similarity and DNA analysis is discussed in light of these results.

Recent studies have claimed to detect interaction between candidate genes and specific environmental factors (Genotype × Environment interaction, G × E) in susceptibility to psychiatric disorder. The objective of the present study was to examine possible artifacts that could explain widely publicized findings. The additive effects of candidate genes and measured environment on liability to disorder were simulated under a model that allowed for mixture of distributions in liability conditional on genotype and environment. Simulated liabilities were dichotomized at a threshold value to reflect diagnosis of disorder. Multiple blocks of simulated data were analyzed by standard statistical methods to test for the main effects and interactions of genes and environment on outcome. The main outcome of this study was simulated liabilities and diagnoses of major depression and antisocial behavior. Analysis of the dichotomized data by logistic regression frequently detected significant G × E interaction even though none was present for liability. There is therefore reason to question the biological significance of published findings.

Previous twin studies have indicated that approximately 25% of the variation in life span can be attributed to genetic factors and recent studies have also suggested a moderate clustering of extreme longevity within families. Here we discuss various definitions of extreme longevity and some analytical approaches with special attention to the challenges due to censored data. Lexis diagrams are provided for the Danish, Dutch, Finnish, Italian, Norwegian, and Swedish Twin registries hereby outlining possibilities for longevity studies within GenomEUtwin. We extend previous analyses of lifespan for the Danish 1870–1900 twin cohorts to include the new 1901–1910 cohorts, which are consistent with the previous findings. The size of the twin cohorts in GenomEUtwin and the existence of population-based, nationwide health and death registers make epidemiological studies of longevity very powerful. The combined GenomEUtwin sample will also allow detailed age-specific heritability analyses of lifespan. Finally, it will provide a resource for identifying unusual sibships (i.e., dizygotic twin pairs) where both survived to extreme ages, as a basis for discovering genetic variants of importance for extreme survival.

Hardy–Weinberg equilibrium (HWE) is the state of the genotypic frequency of two alleles of one autosomal gene locus after one discrete generation of random mating in an indefinitely large population: if the alleles are A and a with frequencies p and q(=1-p), then the equilibrium gene frequencies are simply p and q and the equilibrium genotypic frequencies for AA, Aa and aa are p2, 2pq and q2. It was independently identified in 1908 by G. H. Hardy and W. Weinberg after earlier attempts by W. E. Castle and K. Pearson. Weinberg, well known for pioneering studies of twins, made many important contributions to genetics, especially human genetics. Existence of this equilibrium provides a reference point against which the effects of selection, linkage, mutation, inbreeding and chance can be detected and estimated. Its discovery marked the initiation of population genetics.

Both genetic and environmental factors affect smoking initiation and maintenance, but less is known about the genetic architecture of various other smoking-related behaviors. The aim of this study is to examine the genetic architecture of smoking behavior in a large twin cohort. Questionnaires with an extensive smoking history section were mailed to same-sex adult twins of the Finnish twin cohort. The final study population included 2923 monozygotic and 6018 dizygotic twin pairs aged 24 to 88 years. Two-stage bivariate genetic modeling of age at initiation with amount smoked (less than 20 cigarettes per day vs. 20 or more) and age at initiation with smoking cessation was done by using the Mx statistical package. For men the heritability estimate for age at initiation was .59 (95% confidence interval [CI] .49–.69), for amount smoked .54 (95% CI .45–.62) and for smoking cessation .58 (95% CI .50–.65). For women the heritability estimates were .36 (95% CI .28–.43), .61 (95% CI .46–.70) and .50 (95% CI .39–.60), respectively. The genetic correlations between age at initiation and amount smoked or smoking cessation were at most .22 in magnitude, indicating that genetic influences in age at initiation accounted for at most about 4% of the genetic factors in amount smoked or in cessation. Genetic factors are important in amount smoked and smoking cessation and they are largely independent of genetic influences on age at initiation. This has implications for defining phenotypes in searches for genes underlying smoking behaviors.

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources — the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping — allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

Understanding the genetic and environmental contributions to measures of brain structure such as surface area and cortical thickness is important for a better understanding of the nature of brain-behavior relationships and changes due to development or disease. Continuous spatial maps of genetic influences on these structural features can contribute to our understanding of regional patterns of heritability, since it remains to be seen whether genetic contributions to brain structure respect the boundaries of any traditional parcellation approaches. Using data from magnetic resonance imaging scans collected on a large sample of monozygotic and dizygotic twins in the Vietnam Era Twin Study of Aging, we created maps of the heritability of areal expansion (a vertex-based area measure) and cortical thickness and examined the degree to which these maps were affected by adjustment for total surface area and mean cortical thickness. We also compared the approach of estimating regional heritability based on the average heritability of vertices within the region to the more traditional region-of-interest (ROI)-based approach. The results suggested high heritability across the cortex for areal expansion and, to a slightly lesser degree, for cortical thickness. There was a great deal of genetic overlap between global and regional measures for surface area, so maps of region-specific genetic influences on surface area revealed more modest heritabilities. There was greater inter-regional variability in heritabilities when calculated using the traditional ROI-based approach compared to summarizing vertex-by-vertex heritabilities within regions. Discrepancies between the approaches were greatest in small regions and tended to be larger for surface area than for cortical thickness measures. Implications regarding brain phenotypes for future genetic association studies are discussed.

The Netherlands Twin Register (NTR) was established around 1987 at the Vrije Universiteit in Amsterdam, the Netherlands. The current article summarizes the longitudinal genetic analyses of maternal and paternal ratings of twins' behavior as a function of the sex of the children for the traits of aggression (AGG), attention problems (AP), anxious/depression (ANX), internalizing behavior (INT) and externalizing behavior (EXT). We found that genetic influences are the most important factor in explaining individual differences in these traits. For most phenotypes, influences of genetic factors fluctuate throughout development, with the exception of AP, for which genetic influences remain of similar magnitude. Changes in genetic influences parallel those in shared environmental influences, while nonshared environmental influences remain relatively constant. Around 10% to 20% of the variance is accounted for by parent-specific shared environment, which includes rater bias. For all phenotypes, stability throughout childhood is accounted for by genetic and shared environmental factors, while nonshared environmental influences are mainly age/measurement specific. About 15% of the phenotypic stability is accounted for by rater-specific shared environmental influences, which include rater bias. In conclusion, between ages 3 and 12 genetic factors are the most important cause of individual differences in emotional and behavioral problems.

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King’s College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several ‘omic’ technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the ‘TwinsUK’ resource with the scientific community — interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.

We reanalyze previously published data on 309 MZ and 333 DZ twin pairs aged 25 to 74 years from the MIDUS survey, a nationally representative archived sample, to examine how much of the genetic covariance between a general factor of personality (GFP), a lower-order life history factor, and a general physical and mental health factor, is of the nonadditive variety. We found nonadditive genetic effects (D) could not be ruled out as a contributor to the shared variance of these three latent factors to a Super-K Life History factor. We suggest these genetic correlations support the view that a slow (K-selected) life history strategy, good health, and the GFP coevolved and are mutually coadapted through directional selection.

The Vietnam Era Twin (VET) Registry is composed of 7369 middle-aged male-male twin pairs both of whom served in the military during the time of the Vietnam conflict (1965–1975). The Registry is a United States Department of Veterans Affairs resource that was originally constructed from military records; the Registry has been in existence for more than 15 years. It is one of the largest national twin registries in the US and currently has subjects living in all 50 states. Initially formed to address questions about the long-term health effects of service in Vietnam the Registry has evolved into a resource for genetic epidemiologic studies of mental and physical health conditions. The management and administration of the VET Registry is described with particular attention given to the processes involved with database maintenance and study coordination. Several waves of mail and telephone surveys have collected a wealth of health-related information on Registry twins. More recent data collection efforts have focused on specific sets of twin pairs and conducted detailed clinical or laboratory testing. New Registry initiatives for the future include the construction of a web site and the development of a DNA repository.

In studies on the Finnish Twin Cohorts, genetic and environmental determinants of common, complex diseases, and their behavioral risk factors have been investigated in Finland. In 1974, the older twins were identified, with a total of 13,888 like-sexed pairs of known zygosity. They have participated since 1975 in mail surveys, clinical examinations for subsamples, have been used to recruit families, and have been followed up for morbidity using national medical registers. Opposite twin pairs were added later. Two longitudinal studies of adolescent twins and their families, known as the FinnTwin12 and FinnTwin16 studies, have focused on determinants of health-related behaviors and disease in adolescents and young adults. This article describes current, ongoing data collection and analyses.