The objective of this study was to estimate the magnitude of genetic and environmental influences to variation in adolescent neuroticism as a function of age and sex. Neuroticism was assessed using the Amsterdamse Biografische Vragenlijst (ABV): a self-report personality instrument similar in content to the Eysenck Personality Questionnaire. Genetic modeling procedures, including age as modifier, were fitted to the total sample of 3301 Dutch adolescent twins aged 12 to 17 years (mean age 15.5). Significant influences of additive genetic factors (.59, 95% confidence intervals [CI] .54–.63) and unshared environmental factors (.41, 95% CI .37–.45) were found. Our data did not support a role of shared environment. Results showed that different genes may influence variation in neuroticism between girls and boys. No interaction was found between the variance components and age. Results generally support prior findings in adults and young children that neuroticism is influenced principally by additive genetic and unique environmental factors. The magnitude of the genetic component appears higher in the present sample of adolescents than in most studies of adults. The present study suggests that, in adolescence, different genes are expressed in boys and girls.

As the success rates of IVF clinics improve, one of the adverse consequences is the increased incidence of twins, due largely to the number of embryos transferred. Even if the number of embryos transferred is restricted to two, the twinning rate can exceed 40% of the pregnancies. An obvious way to reduce this high twin rate would be to transfer only one embryo. This would require that cryopreservation of the supernumerary embryos be efficacious enough so that the chance of achieving an ongoing pregnancy is not diminished by transferring a single embryo in the stimulated cycle. Previous studies utilising embryos on day 2 and 3 of development have shown that the pregnancy rates can be acceptable (about 40%) and that the cumulative rate can be up to 60%. Most of these studies, however, do not include a comparison with the cumulative pregnancy rate with two embryos transferred in the stimulated cycle. Therefore, the efficacy has not been proven. We present clinical data from the past few years to illustrate the increase in success rates and the concomitant increase in twinning rates. The increased success in the cryopreservation program has enabled us to trial a single embryo transfer program and compare the results to the transfer of two embryos. The results strongly suggest that the transfer of a single embryo is the better clinical option.

Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 × 10−7). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 × 10−6). Several of the top ranking probes (p < 1 × 10−4) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 × 10−15) developmental process (GO:0032502, p = 2.96 × 10−12), and cellular developmental process (GO:0048869, p = 1.96 × 10−12). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder.

After a long continuous decrease, the twinning and higher multifetal rates in many developed countries have increased during the last 2 to 3 decades. This change has been attributed to delayed childbearing and to increased use of subfertility treatments, particularly in women over 35 years of age. In this study we analyze how these new trends depend on changes in the effect of maternal age on the rates of multiple maternities. Our study is based on data for England and Wales for the period 1938 to 2003. The temporal variations show a decreasing trend to a trough around 1980 and after that a steady increase. This increase was more marked for higher multifetal rates and was particularly high for quadruplets. Furthermore, we identified changes in the age-specific rates resulting in increased levels for older mothers. These findings are in good agreement with our results from Nordic populations.

Research on twin-singleton differences in externalizing and internalizing problems in childhood is largely cross-sectional and yields contrasting results. The goal of this study was to compare developmental trajectories of externalizing and internalizing problems in 6- to 12-year-old twins and singletons. Child Behavior Checklist (CBCL) maternal reports of externalizing and internalizing problems were obtained for a sample of 9651 twins from the Netherlands Twin Register and for a representative general population sample of 1351 singletons. Latent growth modeling was applied to estimate growth curves for twins and singletons. Twin-singleton differences in the intercepts and slopes of the growth curves were examined. The developmental trajectories of externalizing problems showed a linear decrease over time, and were not significantly different for twins and singletons. Internalizing problems seem to develop similarly for twins and singletons up to age 9. After this age twins' internalizing symptoms start to decrease in comparison to those of singletons, resulting in less internalizing problems than singletons by the age of 12 years. Our findings confirm the generalizability of twin studies to singleton populations with regard to externalizing problems in middle and late childhood. The generalizability of studies on internalizing problems in early adolescence in twin samples should be addressed with care. Twinship may be a protective factor in the development of internalizing problems during early adolescence.

The relationship between the genetic and environmental risk factors for alcohol use disorders (AUD) detected in Swedish medical, pharmacy, and criminal registries has not been hitherto examined. Prior twin studies have varied with regard to the detection of shared environmental effects and sex differences in the etiology of AUD. In this report, structural equation modeling in OpenMx was applied to (1) the three types of alcohol registration in a population-based sample of male–male twins and reared-together full and half siblings (total 208,810 pairs), and (2) AUD, as a single diagnosis, in male–male, female–female, and opposite-sex (OS) twins and reared-together full and half siblings (total 787,916 pairs). An independent pathway model fit best to the three forms of registration and indicated that between 70% and 92% of the genetic and 63% and 98% of the shared environmental effects were shared in common with the remainder unique to each form of AUD registration. Criminal registration had the largest proportion of unique genetic and environmental factors. The best fit model for AUD estimated the heritability to be 22% and 57%, respectively, in females and males. Both shared (12% vs. 6%) and special twin environment (29% vs. 2%) were substantially more important in females versus males. In conclusion, AUD ascertained from medical, pharmacy, and criminal Swedish registries largely share the same genetic and environmental risk factors. Large sex differences in the etiology of AUD were seen in this sample, with substantially stronger familial environmental and weaker genetic effects in females versus males.

The purpose of this study was to investigate whether there is any association between preeclampsia and eNOS, DDAH, and VEGF gene polymorphisms, and also to search for a possible association between haplotypes in eNOS, DDHA, and VEGF genes and the risk for preeclampsia. DNA was extracted from whole blood of 223 preeclampsia patients and 237 healthy pregnant women. The genotypes were analyzed by a single base primer extension assay using a SNaPShot assay kit. Results were analyzed with the Student's t-test, Chi-square test, and Logistic regression analysis. Haplotype analyses were performed using Haploview 3.2 version. There were no significant differences in genotype or allele frequencies of eNOS, DDAH, and VEGF gene polymorphisms between preeclampsia patients and controls. No increase in the risk of preeclampsia for those genes was observed under any model of inheritance and there were no statistically significant associations between any haplotypes and preeclampsia risk. Polymorphisms in eNOS, DDAH, and VEGF gene do not seem to be risk factors for preeclampsia.

Aggressive behavior is highly heritable, while environmental influences, particularly early in life, are also important. Epigenetic mechanisms, such as DNA methylation, regulate gene expression throughout development and adulthood, and may mediate genetic and environmental effects on complex traits. We performed an epigenome-wide association study (EWAS) to identify regions in the genome where DNA methylation level is associated with aggressive behavior. Subjects took part in longitudinal survey studies from the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2004 and 2011 (N = 2,029, mean age at blood sampling = 36.4 years, SD = 12.4, females = 69.2%). Aggressive behavior was rated with the ASEBA Adult Self-Report (ASR). DNA methylation was measured in whole blood by the Illumina HM450k array. The association between aggressive behavior and DNA methylation level at 411,169 autosomal sites was tested. Association analyses in the entire cohort showed top sites at cg01792876 (chr8; 116,684,801, nearest gene = TRPS1, p = 7.6 × 10−7, False discovery rate (FDR) = 0.18) and cg06092953 (chr18; 77,905,699, nearest gene = PARD6G-AS1, p = 9.0 ×10−7, FDR = 0.18). Next, we compared methylation levels in 20 pairs of monozygotic (MZ) twins highly discordant for aggression. Here the top sites were cg21557159 (chr 11; 107,795,699, nearest gene = RAB39, p = 5.7 × 10−6, FDR = 0.99), cg08648367 (chr 19; 51,925,472, nearest gene = SIGLEC10, p = 7.6 × 10−6, FDR = 0.99), and cg14212412 (chr 6; 105,918,992, nearest gene = PREP, p = 8.0 × 10−6, FDR = 0.99). The two top hits based on the entire cohort showed the same direction of effect in discordant MZ pairs (cg01792876, Pdiscordant twins = 0.09 and cg06092953, Pdiscordant twins = 0.24). The other way around, two of the three most significant sites in discordant MZ pairs showed the same direction of effect in the entire cohort (cg08648367, Pentire EWAS = 0.59 and cg14212412, Pentire EWAS = 3.1 × 10−3). Gene ontology analysis highlighted significant enrichment of various central nervous system categories among higher-ranking methylation sites. Higher-ranking methylation sites also showed enrichment for DNase I hypersensitive sites and promoter regions, showing that DNA methylation in peripheral tissues is likely to be associated with aggressive behavior.

Previous studies have looked at the structure of attention-deficit/hyperactivity disorder (ADHD) using latent class analysis (LCA) of Child Behavior Checklist (CBCL) or Diagnostic and Statistical Manual of Mental Disorders (DSM) symptom structure. These studies have identified distinct classes of children with inattentive, hyperactive, or combined subtypes and have used these classes to refine genetic analyses. The objective of the current report is to determine if the latent class structure of ADHD subtypes is consistent across informant using the Conners' Rating Scales (CRS). LCA was applied to CRS forms from mother, father, and teacher reports of 1837, 1329 and 1048 latency aged Dutch twins, respectively. The optimal solution for boys was a 5-class solution for mothers, a 3-class solution for fathers, and a 4-class solution for teachers. For girls, a 4-class solution for mothers and a 3-class for fathers and teachers was optimal. Children placed into a class by one informant had markedly increased odds ratio of being placed into the same or similar class by the other informants. Results from LCA using Dutch twins with the CRS show stability across informants suggesting that more stable phenotypes may be accessible for genotyping using a multi-informant approach.

The nature of Generalized Anxiety Disorder (GAD) and worry across the lifespan remains incompletely understood. We investigated genetic and environmental influences on GAD and the proportion of genetic and environmental variation in GAD that is shared with neuroticism in older adult twins. Participants included 1618 monozygotic and 2291 same-sexed dizygotic twin pairs from the Swedish Twin Registry aged 55 to 74. Participants provided personality information in 1973 and also participated in a telephone screening between 1998 and 2002 that included an assessment for lifetime GAD. Univariate biometric models indicated that both GAD and neuroticism were moderately heritable (.27 and .47, respectively), while the balance of variation reflected environmental factors unique to the individual. Bivariate analyses indicated that approximately one third of the genetic influences on GAD were in common with genetic influences on neuroticism, while individual specific environmental influences were virtually unshared between GAD and neuroticism. Analyses of sex effects suggested that men and women differed in the frequency of lifetime GAD and level of neuroticism; however, no sex differences for genetic and environmental influences for either trait were identified.

Perinatal mortality is increased considerably in multiple pregnancies compared to singleton pregnancies, with single intrauterine fetal demise (sIUFD) presenting a rare but unique perinatal problem. Monochorionic pregnancies are at particular risk of sIUFD due to bidirectional inter-twin placental vascular anastomoses. The resulting inter-twin blood flow can become unbalanced, causing acute and chronic inter-twin transfusion and profound anemia secondary to fetal exsanguination into the low-pressure circulation of the dead fetus. If the sIUFD occurs after 14 weeks’ gestation it is believed to have the most significant effect on the continuing pregnancy as the co-twin is at increased risk of preterm delivery, long-term neurological complications, and death. This article will focus on fetal brain injury in the surviving co-twin in the case of sIUFD, as it is the most common kind of injury in sIUFD, and one which concerns parents and may be the basis for terminating the pregnancy. We will outline how these brain injuries are thought to occur and describe potential pathophysiological mechanisms. We will discuss risk factors for brain injury in cases of sIUFD, including: chorionicity, cause of the sIUFD (spontaneous or secondary to an underlying pathological process such as twin-to-twin transfusion syndrome), gestation of delivery and how to prevent brain injury in the co-twin. We also review modes of imaging, discuss the difficulties in predicting the long-term outcome for co-twin survivors, and highlight the dearth of research in this area.

Endometriosis is a complex disease that affects 6–10% of women in their reproductive years and 20–50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with ‘All’ (p = .066) and ‘Grade_B’ (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.

Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.

Boys and girls may display different styles of aggression. The aim of this study was to identify subtypes of aggression within the Child Behavior Checklist (CBCL) aggression scale, and determine their characteristics for both sexes. Maternal CBCL ratings of 7449 7-year-old twin pairs were analyzed using principal components analyses to identify sub- types of aggression, and structural equation modeling to carry out genetic analyses. Two aggression subtypes were identified: relational and direct aggression. The correlation between these subtypes was .58 for boys and .47 for girls. Boys had higher mean scores for both subtypes of aggression, but sex differences were largest for direct aggression. For relational aggression, 66% of the variance was due to additive genetic influences, 16% to shared environment and 18% to nonshared environment. For direct aggression, additive genetic effects accounted for 53% of the variance in males and 60% in females, shared environment explained 23% of the variance in males and 13% in females, and nonshared environmental effects explained 24% of the variance in males and 27% in females. Covariance between the aggression subtypes was mostly accounted for by additive genetic (55% for boys, 58% for girls) and shared environmental influences (33% for boys, 30% for girls). Direct and relational aggression were both influenced by one underlying set of shared environmental factors, but only partly by the same genes (the genetic correlation was .54 for boys and .43 for girls). These findings may have implications for how aggressive behavior should be assessed in boys and girls.

The choice of where to live would appear to be determined by a combination of economic constraints and personal preferences. We have tested how far this choice is affected by the continuing effects of the environment shared within families, and genetic variation between people, using data from twin studies conducted in Australia. The addresses provided by study participants were categorized as urban, suburban and nonurban, and data were analyzed in three adult age groups. There were significant effects of both shared environment and genes, and the balance between them was affected by both sex and age. Shared environment accounted for some 50% of variation in the youngest group, but only about 10% in the oldest. As shared environmental effects decreased, additive genetic effects increased. These results have implications for internal migration of people within countries and, over the long term, for gene flow within and between populations. They may also be pertinent to the different prevalences of certain psychiatric diseases between city and country locations. Comparisons between countries with different demography are needed to confirm and further characterize these effects.

Now celebrating its 26th year of existence, the Vietnam Era Twin Registry continues to be one of the largest national samples of adult twins in the United States. The Registry twin member population is composed of 7,369 US male–male twin pair Veterans (14,738 total individuals) who served on active duty in the military during the Vietnam conflict (1964–1975). The Registry also maintains a register, data repository, and a biospecimen repository. Details on the operations of the Registry are described, as well as an overview of specific studies. Registry maintenance activities are also described, including the updating of contact information and vital status. Future plans include expanding the biospecimen repository and obtaining input from twins about study methods and diseases and conditions they would like to see investigated.

The Southern California Twin Register at the University of Southern California (USC) was initiated in 1984 and continues to provide an important resource for studies investigating genetic and environmental influences on human behavior. This article provides an update on the current register and its potential for future twin studies using recruitment through school district databases and voter records. An overview is also provided for an ongoing longitudinal twin study investigating the development of externalizing psychopathology from childhood to young adulthood, the USC Study of Risk Factors for Antisocial Behavior. Characteristics of the twins and their families are presented, including recruitment and participation rates, as well as attrition analyses and a summary of key findings to date.

Political sophistication is a concept that encompasses political reasoning, the coherence of people's issue attitudes, and their knowledge of political processes. To what extent is political sophistication affected by genes and environments? Do these distinct but related measures of sophistication share a common genetic structure? We analyze survey data collected from participants in the Minnesota Twin Registry to estimate influences of genes and environments on variables used to measure political sophistication. Additive genetic factors explain 48–76% of the variation in educational attainment, political interest, and political knowledge, while dominance genetics influence 28% of the variance of ideological consistency. Multivariate analyses show that, although these measures share common genetic and unique environmental factors to a modest extent, much of the variance is explained by specific genetic and unique environmental factors. Ideological consistency appears to be mostly distinct from the other measures, as it is strongly accounted for by unique environmental influences.

Depression and reduced heart rate variability (HRV) are predictors of coronary artery disease (CAD), and highly correlated with each other. However, little is known to what extend this correlation can be explained by common genetic components. We examined 198 middle-aged male twins (121 monozygotic and 77 dizygotic) from the Vietnam Era Twin Registry. Current depressive symptoms were assessed using the Beck Depression Inventory-II and HRV was assessed on 24-hour electrocardiographic Holter recordings. Five frequency domain variables were used, including ultra low frequency (ULF), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TPow). Structural equation modeling was used to estimate shared genetic effects for depressive symptoms and the HRV frequency domains. Both depressive symptoms (h2=.5) and all measurements of HRV showed high heritability (h2=.43-.63). A significant inverse correlation was found between depressive symptoms and all HRV indices except LF and HF, with the highest coefficient (r) for TPow (r = −.24, P = .01) and ULF (r = −.24, P = .01). Bivariate genetic modeling revealed significant genetic correlations between depressive symptoms and TPow (rA = −.21, P = .04), as well as ULF (rA = −.23, P = .02). Of the total covariance between depressive symptoms and these two HRV indices, over 80% was due to the same genetic factors. In conclusion, depressive symptoms are associated with decreased HRV and this association is due, in large part, to a shared genetic effect. These results suggest that a common neurobiological dysfunction links depression and autonomic dysregulation.

Objective: To evaluate the perinatal outcome of MC twins with selective IUGR (sIUGR).

Study design: A prospective study, which included three groups of MC twins: Group A, uncomplicated MC twin pregnancies (n = 91); group B, sIUGR with normal umbilical artery Doppler (n = 19); and group C, sIUGR with abnormal (absence or reversed EDV) umbilical artery Doppler (n = 18). The latter were routinely hospitalized in the high-risk ward under strict surveillance.

Results: Neonatal outcome of fetuses complicated with sIUGR and normal Doppler was similar to controls. Neonates born to pregnancies complicated by sIUGR and abnormal Doppler had significantly increased incidence of CNS findings, RDS, NEC, sepsis, and neonatal death compared to controls. Adverse outcome in this group was independently associated only with gestational age at birth.

Conclusion: The perinatal outcomes of MC twins complicated with sIUGR and normal Doppler are similar to uncomplicated MC pregnancies. MC twins with sIUGR and abnormal Doppler have reasonable outcomes, yet significantly more neonatal complications compared to non-complicated MC twins.