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Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.
There are research questions whose answers require record linkage of multiple databases that may be characterized by limited options for full data sharing. For this purpose, the Open Data Infrastructure for Social Science and Economic Innovations (ODISSEI) consortium has supported the development of the ODISSEI Secure Supercomputer (OSSC) platform that allows researchers to link cohort data to data from Statistics Netherlands and run large-scale analyses in a high-performance computing (HPC) environment. Here, we report a successful record linkage genomewide association (GWA) study on expenditure for total health, mental health, primary and hospital care, and medication. Record linkage for genotype data from 16,726 participants from the Netherlands Twin Register (NTR) with data from Statistics Netherlands was accomplished in the secure OSSC platform, followed by gene-based tests and estimation of total and single nucleotide polymorphism (SNP)-based heritability. The total heritability of expenditure ranged between 29.4% (SE 0.8) and 37.5% (SE 0.8), but GWA analyses did not identify SNPs or genes that were genomewide significantly associated with health care expenditure. SNP-based heritability was between 0.0% (SE 3.5) and 5.4% (SE 4.0) and was different from zero for mental health care and primary care expenditure. We conclude that successfully linking genotype data to administrative health care expenditure data from Statistics Netherlands is feasible and demonstrates a series of analyses on health care expenditure. The OSSC platform offers secure possibilities for analyzing linked data in large scale and realizing sample sizes required for GWA studies, providing invaluable opportunities to answer many new research questions.
Research suggests that cannabis use negatively impacts on onset and outcome of schizophrenia. Possible effects in mood disorders have received little investigation. The first study analysing the influence of cannabis exposure on clinical and social treatment outcomes within a bipolar disorder (BP) population during 1 year of treatment is presented.
3684 patients were enrolled in an observational study when psychotropic treatment for mania was initiated/changed. The influence of cannabis exposure on baseline-corrected clinical and social treatment outcome measures was examined. Mediating effects of six variables on associations between cannabis and outcome measures were investigated further.
Over 12 months of treatment, cannabis users exhibited higher levels of BP overall illness severity, mania and psychosis, and less severe depression symptoms compared to non-users. These associations were most frequently mediated by abuse of alcohol and other substances. Users more frequently abused alcohol and other substances; these associations were not mediated by other variables. Cannabis users engaged in more social activities but had a higher probability of not having a relationship and fewer dependents to care for. Associations with activities and dependents to care for were mediated by various variables, whereas no variables mediated the association with not having a relationship.
Cannabis use impacts on clinical outcomes in patients with BP, with a modest impact on social outcomes. More research is required to further elucidate the mechanism by which cannabis exerts its influence. Understanding the associations between cannabis use and outcome measures may offer valuable insights into treatment strategies.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
The monocyte–lymphocyte ratio (MLR) is a useful biomarker for disease development, but little is known about the extent to which genetic and environmental factors influence MLR variation. Here, we study the genetic architecture of MLR and determine the influence of demographic and lifestyle factors on MLR in data from a Dutch non-patient twin-family population. Data were obtained in 9,501 individuals from the Netherlands Twin Register. We used regression analyses to determine the effects of age, sex, smoking, and body mass index (BMI) on MLR and its subcomponents. Data on twins, siblings and parents (N = 7,513) were analyzed by genetic structural equation modeling to establish heritability and genome wide single nucleotide polymorphism (SNP) data from a genotyped subsample (N = 5,892) and used to estimate heritability explained by SNPs. SNP and phenotype data were also analyzed in a genome-wide association study to identify the genes involved in MLR. Linkage disequilibrium (LD) score regression and expression quantitative trait loci (eQTL) analyses were performed to further explore the genetic findings. Results showed that age, sex, and age × sex interaction effects were present for MLR and its subcomponents. Variation in MLR was not related to BMI, but smoking was positively associated with MLR. Heritability was estimated at 40% for MLR, 58% for monocyte, and 58% for lymphocyte count. The Genome-wide association study (GWAS) identified a locus on ITGA4 that was associated with MLR and only marginally significantly associated with monocyte count. For monocyte count, additional genetic variants were identified on ITPR3, LPAP1, and IRF8. For lymphocyte count, GWAS provided no significant findings. Taking all measured SNPs together, their effects accounted for 13% of the heritability of MLR, while all known and identified genetic loci explained 1.3% of variation in MLR. eQTL analyses showed that these genetic variants were unlikely to be eQTLs. In conclusion, variation in MLR level in the general population is heritable and influenced by age, sex, and smoking. We identified gene variants in the ITGA4 gene associated with variation in MLR. The significant SNP-heritability indicates that more genetic variants are likely to be involved.
Genetic–epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample.
In an extended twin-family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria.
Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects.
Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies.
We identified the genetic variants for eye color by Genome-Wide Association Study (GWAS) in a Dutch Caucasian family-based population sample and examined the genetic correlation between hair and eye color using data from unrelated participants from the Netherlands Twin Register. With the Genome-wide Complex Trait Analysis software package, we found strong genetic correlations between various combinations of hair and eye colors. The strongest positive correlations were found for blue eyes with blond hair (0.87) and brown eyes with dark hair (0.71), whereas blue eyes with dark hair and brown eyes with blond hair showed the strongest negative correlations (-0.64 and -0.94, respectively). Red hair with green/hazel eyes showed the weakest correlation (-0.14). All analyses were corrected for age and sex, and we explored the effects of correcting for principal components (PCs) that represent ancestry and describe the genetic stratification of the Netherlands. When including the first three PCs as covariates, the genetic correlations between the phenotypes disappeared. This is not unexpected since hair and eye colors strongly indicate the ancestry of an individual. This makes it difficult to separate the effects of population stratification and the true genetic effects of variants on these particular phenotypes.
There is a paucity of valid, brief instruments for the assessment of lifetime major depressive disorder (MDD) that can be used in, for example, large-scale genomics, imaging or biomarker studies on depression. We developed the LIfetime Depression Assessment Self-report (LIDAS), which assesses lifetime MDD diagnosis according to DSM criteria, and is largely based on the widely used Composite International Diagnostic Interview (CIDI). Here, we tested the feasibility and determined the sensitivity and specificity for measuring lifetime MDD with this new questionnaire, with a regular CIDI as reference.
Sensitivity and specificity analyses of the online lifetime MDD questionnaire were performed in adults with (n = 177) and without (n = 87) lifetime MDD according to regular index CIDIs, selected from the Netherlands Study of Depression and Anxiety (NESDA) and Netherlands Twin Register (NTR). Feasibility was tested in an additional non-selective, population-based sample of NTR participants (n = 245).
Of the 753 invited persons, 509 (68%) completed the LIDAS, of which 419 (82%) did this online. User-friendliness of the instrument was rated high. Median completion time was 6.2 min. Sensitivity and specificity for lifetime MDD were 85% [95% confidence interval (CI) 80–91%] and 80% (95% CI 72–89%), respectively. This LIDAS instrument gave a lifetime MDD prevalence of 20.8% in the population-based sample.
Measuring lifetime MDD with an online instrument was feasible. Sensitivity and specificity were adequate. The instrument gave a prevalence of lifetime MDD in line with reported population prevalences. LIDAS is a promising tool for rapid determination of lifetime MDD status in large samples, such as needed for genomics studies.
Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
Wellbeing (WB) is a major topic of research across several scientific disciplines, partly driven by its strong association with psychological and mental health. Twin-family studies have found that both genotype and environment play an important role in explaining the variance in WB. Epigenetic mechanisms, such as DNA methylation, regulate gene expression, and may mediate genetic and environmental effects on WB. Here, for the first time, we apply an epigenome-wide association study (EWAS) approach to identify differentially methylated sites associated with individual differences in WB. Subjects were part of the longitudinal survey studies of the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2002 and 2011. WB was assessed by a short inventory that measures satisfaction with life (SAT). DNA methylation was measured in whole blood by the Illumina Infinium HumanMethylation450 BeadChip (HM450k array) and the association between WB and DNA methylation level was tested at 411,169 autosomal sites. Two sites (cg10845147, p = 1.51 * 10−8 and cg01940273, p = 2.34 * 10−8) reached genome-wide significance following Bonferonni correction. Four more sites (cg03329539, p = 2.76* 10−7; cg09716613, p = 3.23 * 10−7; cg04387347, p = 3.95 * 10−7; and cg02290168, p = 5.23 * 10−7) were considered to be genome-wide significant when applying the widely used criterion of a FDR q value < 0.05. Gene ontology (GO) analysis highlighted enrichment of several central nervous system categories among higher-ranking methylation sites. Overall, these results provide a first insight into the epigenetic mechanisms associated with WB and lay the foundations for future work aiming to unravel the biological mechanisms underlying a complex trait like WB.
Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to pre-disposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10−8), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
Do DSM-IV diagnostic criteria for major depression (MD) in Chinese and Western women perform in a similar manner?
The CONVERGE study included interview-based assessments of women of Han Chinese descent with treated recurrent MD. Using Mplus software, we investigated the overall degree of between-sample measurement invariance (MI) for DSM-IV diagnostic criteria for MD in the CONVERGE sample and samples selected from four major Western studies from the USA and Europe matched to the inclusion criteria of CONVERGE. These analyses were performed one pair at a time. We then compared the results from CONVERGE paired with Western samples to those obtained when examining levels of MI between pairs of the Western samples.
Assuming a single factor model for the nine diagnostic criteria for MD, the level of MI based on global fit indexes observed between the CONVERGE and the four Western samples was very similar to that seen between the Western samples. Comparable results were obtained when using a two-factor structure for MI testing when applied to the 14 diagnostic criteria for MD disaggregated for weight, appetite, sleep, and psychomotor changes.
Despite differences in language, ethnicity and culture, DSM criteria for MD perform similarly in Chinese women with recurrent MD and comparable subjects from the USA and Europe. The DSM criteria for MD may assess depressive symptoms that are relatively insensitive to cultural and ethnic differences. These results support efforts to compare findings from depressed patients in China and Western countries.
The influence of genetic factors on major depressive disorder is lower than on other psychiatric disorders. Heritability estimates mainly derive from cross-sectional studies, and knowledge on the longitudinal aetiology of symptoms of anxiety and depression (SxAnxDep) across the lifespan is limited. We aimed to assess phenotypic, genetic and environmental stability in SxAnxDep between ages 3 and 63 years.
We used a cohort-sequential design combining data from 49 524 twins followed from birth to age ⩾20 years, and from adolescence into adulthood. SxAnxDep were assessed repeatedly with a maximum of eight assessments over a 25-year period. Data were ordered in 30 age groups and analysed with longitudinal genetic models.
Over age, there was a significant increase during adolescence in mean scores with sex differences (women>men) emerging. Heritability was high in childhood and decreased to 30–40% during adulthood. This decrease in heritability was due to an increase in environmental variance. Phenotypic stability was moderate in children (correlations across ages ~0.5) and high in adolescents (r = 0.6), young adults (r = 0.7), and adults (r = 0.8). Longitudinal stability was mostly attributable to genetic factors. During childhood and adolescence there was also significant genetic innovation, which was absent in adults. Environmental effects contributed to short-term stability.
The substantial stability in SxAnxDep is mainly due to genetic effects. The importance of environmental effects increases with age and explains the relatively low heritability of depression in adults. The environmental effects are transient, but the contribution to stability increases with age.
Cross-sectional and longitudinal studies have shown a positive association between attention deficit hyperactivity disorder (ADHD) and problematic alcohol use in adults. To what extent this association is explained by genetic and environmental factors is largely unknown.
Data on ADHD and alcohol consumption were collected by self-report in 6024 adult Dutch twins. ADHD symptoms were assessed by three subscales of the Conners' Adult ADHD Rating Scales – Self-Report: Screening Version (CAARS–S:SV): inattentiveness, hyperactivity and the ADHD index (ADHD-I). Problem drinking was defined as at least two self-reported alcohol-related problems on the CAGE questionnaire. Structural equation modelling was applied to the bivariate twin data to estimate genetic and environmental influences.
Heritability of ADHD symptoms ranged between 32% and 40% and heritability of problem drinking was 50%. The positive correlation between ADHD symptoms and problem drinking was confirmed in this general population sample, with phenotypic correlations between 0.20 and 0.28 and genetic correlations between 0.39 and 0.50. Phenotypic correlations are primarily (61–100%) explained by genetic influences with non-shared environmental influences explaining the remaining covariance. No significant quantitative or qualitative gender differences in covariance structure were found.
This study convincingly shows that ADHD symptoms and problem drinking are moderately but significantly correlated in adults and that genetic correlations are primarily underlying this association. This suggests that early interventions are required to prevent adolescents with ADHD from developing problematic levels of alcohol use. Furthermore, clinicians who treat alcohol-dependent patients should be aware that the patient may have a co-morbid condition of ADHD; integrated interventions are required.
Until recently, hoarding was considered an obsessive–compulsive symptom (OCS). However, current evidence suggests that these two phenotypes may be clinically, and perhaps etiologically, distinct. Both hoarding and OCS have a genetic etiology, but the degree of unique and shared genetic contributions to these phenotypes has not been well studied.
Prevalence rates were assessed for hoarding and OCS in a sample of adult twin pairs (n = 7906 twins) and their family members from the Netherlands Twin Register (total sample = 15 914). Using Mplus, genetic analyses using liability threshold models were conducted for both phenotypes, for their co-morbidity, and for specific hoarding symptoms (cluttering, discarding and acquiring).
Of the total sample, 6.7% met criteria for clinically significant hoarding; endorsement of all three hoarding symptoms was ⩾79%. Men had slightly higher rates than women. Also, 5.7% met criteria for clinically significant OCS; rates were similar in males and females. Genetic factors accounted for 36% of the variance for hoarding and 40% of the variance for OCS. The genetic correlation between hoarding and OCS was 0.10. There was no evidence of sex-specific genetic contributions for hoarding or OCS. There was evidence for a genetic contribution to all hoarding symptom subtypes. Only cluttering showed evidence of a contribution from the shared environment.
OCS and hoarding are common in this population-based sample, have prevalence rates similar to those previously reported, and show significant heritability. Genetic factors contributed to the co-morbidity of both traits, although the genetic correlation between them was low.
Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.