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.

Alcohol dependence symptoms and consumption measures were examined for stability and heritability. Data were collected from 12,045 individuals (5376 twin pairs, 1293 single twins) aged 19 to 90 years in telephone interviews conducted in three collection phases. Phases 1 and 2 were independent samples, but Phase 3 targeted families of smokers and drinkers from the Phase 1 and 2 samples. The stability of dependence symptoms and consumption was examined for 1158 individuals interviewed in both Phases 1 and 3 (mean interval = 11.0 years). For 1818 individuals interviewed in Phases 2 and 3 (mean interval = 5.5 years) the stability of consumption was examined. Heritability was examined for each collection phase and retest samples from the selected Phase 3 collection. The measures examined were a dependence score, based on DSM-IIIR and DSM-IV criteria for substance dependence, and a quantity × frequency measure. Measures were moderately stable, with test–retest correlations ranging from .58 to .61 for dependence and from .55 to .64 for consumption. However, the pattern of changes over time for dependence suggested that the measure may more strongly reflect recent than lifetime experience. Similar to previous findings, heritabilities ranged from .42 to .51 for dependence and from .31 to .51 for consumption. Consumption was significantly less heritable in the younger Phase 2 cohort (23–39 years) compared to the older Phase 1 cohort (28–90 years).

The effect of nonresponse on health and lifestyle measures has received extensive study, showing at most relatively modest effects. Nonresponse bias with respect to personality has been less thoroughly investigated. The present study uses data from responding individuals as a proxy for the missing data of their nonresponding family members to examine the presence of nonresponse bias for personality traits and disorders as well as health and lifestyle traits. We looked at the Big Five personality traits, borderline personality disorder (BPD) features, attention-deficit/hyperactivity disorder, Anger, and several measures of health (Body Mass Index, migraine) and lifestyle (smoking, alcohol use). In general, outcomes tend to be slightly more favorable for individuals from highly cooperative families compared to individuals from less cooperative families. The only significant difference was found for BPD features (p = .001). However, the absolute difference in mean scores is very small, less than 1 point for a scale ranging from 0 to 72. In conclusion, survey data on personality, health and lifestyle are relatively unbiased with respect to nonresponse.

A study was made of the seasonal variation in all births, and births according to marital status, multiplicity and birth status (live and still) in Switzerland recorded between 1876 and 1990. To obtain seasonal variation in as pure as possible form, our analyses are based on rates. When comparing the seasonality in data sets showing markedly different levels, standardised indices were used. Assuming the length of pregnancies with twins to be about one month shorter than for pregnancies with singletons, lagged twinning rates were calculated but, in comparison with actual twinning rates, the general seasonal variation remained. Therefore, this study was based on actual twinning rates. A monotonic increase in the amplitude of the seasonal variation in general births was noted for the period 1876–1930, with strong seasonal variation holding for 1921–1980. After that, a marked decline in the amplitude can be observed. Seasonality of both all births and twin maternities showed very similar pattern for the periods 1876–1930 and 1969–1990, with maxima in the spring (March–May) and troughs in late autumn (October–December). Twin maternities showed a strong seasonality for the period 1876–1930, being about 20% higher in March than in October. The twinning rate in the period 1876–1930 was about 2.6 per thousand units higher than in the period 1969–90. For twin maternities there was also a stronger seasonal variation during the earlier period than during the later one. The pattern of the seasonal variation for extramarital births, showing a maximum in February (conceptions in May–June) and a minimum in August (conceptions in November–December) with a difference of no less than 24% was more marked than for the marital births. It seems likely that this seasonality of extra-marital maternities was due mainly to seasonal variation of coital rates and multiple ovulation in the early summer months coinciding with optima of light, temperature and food supply. A strong reduction in the rate of stillbirths (gestational age more than 29 weeks) was observed during the twentieth century. The stillbirth rate declined from about 40 per 1000 in the 1870s to fewer than 5 per 1000 in the 1980s. Irrespective of this strong decline in the stillbirth rate, the same seasonal rhythm was noticed throughout the period with high stillbirth rates among births around March and low rates during the summer and autumn. Twin Research (2000) 3, 189–201.

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.

Our study examines the contribution of genetic and environmental factors (both shared and unique) to frailty, measured using the Rockwood Frailty Index (FI) in a sample of twins from the St Thomas’ UK Adult Twin Registry. The FI was based on 39 items of potential health deficit. Study participants were 3,375 volunteer adult twins (840 monozygotic and 802 dizygotic twin-pairs) 40.0–84.5 years old. First, we used structural equation modeling to estimate the relative contribution of genetics and of the shared and unique environment to variance in FI adjusted for age. In a second analysis, multiple linear regression was used to examine variance in FI as a function of father's occupational class (a component of shared environment and a measure of childhood socioeconomic status [SES]), adjusting for age, birth weight, marital status, and health behaviors (smoking, alcohol consumption, and physical activity). Statistical analyses were conducted using IBM SPSS® Version 22 software and Mx open source software. Findings showed that 45% (95% confidence intervals [CIs] 30–53%) of the inter-individual variation in FI was heritable and 52% (95% CIs 47–57%) was due to the individual's unique environment. Multiple linear regression also showed a small but statistically significant inverse association between father's occupational class and FI, mediated by one's own educational attainment and birth weight. Our results indicate that frailty is both genetically and environmentally determined. Thus, its prevention and management call for a multifaceted approach that includes addressing deleterious environmental factors, some of which, like childhood SES, may act across the life course.

We assessed the heritability of head circumference, an approximation of brain size, in twin-sib families of different ages. Data from the youngest participants were collected a few weeks after birth and from the oldest participants around age 50 years. In nearly all age groups the largest part of the variation in head circumference was explained by genetic differences. Heritability estimates were 90% in young infants (4 to 5 months), 85–88% in early childhood, 83–87% in adolescence, 75% in young and mid adulthood. In infants younger than 3 months, heritability was very low or absent. Quantitative sex differences in heritability were observed in 15- and 18-year-olds, but there was no evidence for qualitative sex differences, that is, the same genes were expressed in both males and females. Longitudinal analysis of the data between 5, 7, and 18 years of age showed high genetic stability (.78 > RG > .98). These results indicate that head circumference is a highly heritable biometric trait and a valid target for future GWA studies.

Although there is substantial evidence from studies of singletons that small size at birth is linked with long-term adverse health effects, until recently little was known as to whether these associations extend to twins. A review of published studies suggests that at present there is little consistent evidence that birthsize in twins is associated with increased morbidity or morality. While, these findings may reflect methodological limitations, it is also argued that they arise as a consequence of the substantially different biology of fetal growth in twins.

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.

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.

Considerable evidence from twin and adoption studies indicates that both genetic and shared environmental factors play a substantial role in the liability to antisocial behavior. Although twin and adoption designs can resolve genetic and environmental influences, they do not provide information about assortative mating, parent–offspring transmission, or the contribution of these factors to trait variation. We examined the role of genetic and environmental factors for conduct disorder (CD) using a twin–parent design. This design allows the simultaneous estimation of additive genetic, shared and individual-specific environmental effects, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission. A retrospective measure of CD was obtained from twins and their parents or guardians in the Virginia Twin Study of Adolescent Behavior Development and its Young Adult Follow up sample. Both genetic and environmental factors play a significant role in the liability to CD. Major influences on individual differences appeared to be additive genetic (38%–40%) and unique environmental (39%–42%) effects, with smaller contributions from the shared environment (18%–23%), assortative mating (~2%), cultural transmission (~2%) and resulting genotype-environment covariance. This study showed significant heritability, which is slightly increased by assortative mating, and significant effects of primarily nonparental shared environment on CD.

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 multiple risk factors for alcohol use (AU) and alcohol use disorders (AUDs) are interrelated through poorly understood pathways, many of which begin in childhood. In this report, the authors seek to develop an empirical, broad-based developmental model for the etiology of AU and AUDs in men. We assessed 15 risk factors in four developmental tiers in 1,794 adult male twins from the Virginia population based twin registry. The best fitting model explained 39% of the variance in late adolescent AU, and 30% of the liability to lifetime symptoms of AUD. AU and AUDs can be best understood as arising from the action and interaction of two pathways reflecting externalizing genetic/temperamental and familial/social factors. Peer group deviance was important in each pathway. Internalizing symptoms played a more minor role. Familial/social factors were especially important influences on AU, while genetic/temperamental factors were more critical for AUDs. We conclude that AU and AUDs in men are complex traits influenced by genetic, family, temperamental, and social factors, acting and interacting over developmental time.

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.

Approximately 60% of children with reading difficulties (RD) meet criteria for at least one co-occurring disorder. The most common of these, attention deficit-hyperactivity disorder (ADHD), occurs in 20–40% of individuals with RD. Recent studies have suggested that genetic influences are responsible. To assess the genetic etiologies of RD and the comorbidity of RD and two ADHD symptom dimensions –– inattention (IN) and hyperactivity/impulsivity (H/I) –– we are conducting the first longitudinal twin study of RD and ADHD. Data from twin pairs in which at least one member of the pair met criteria for proband status for RD at initial assessment, and were reassessed 5 years later, were subjected to DeFries-Fulker (DF) analysis. Analyses of reading composite data indicated that over 60% of the proband deficit at initial assessment was due to genetic influences, and that reading deficits at follow-up were due substantially to the same genetic influences. When a bivariate DF model was fitted to reading performance and IN data, genetic influences accounted for 60% of contemporaneous comorbidity and over 60% of the longitudinal relationship. In contrast, analysis of the comorbidity between reading performance and H/I indicated that common genetic influences accounted for only about 20% of the contemporaneous and about 10% of the longitudinal relationships. Results indicate that (1) genetic influences on RD are substantial and highly stable; (2) the comorbidity between RD and IN is due largely to genetic influences, both contemporaneously and longitudinally; and (3) genetic influences contribute significantly less to the comorbidity between RD and H/I.

The Interplay of Genes and Environment across Multiple Studies (IGEMS) group is a consortium of eight longitudinal twin studies established to explore the nature of social context effects and gene-environment interplay in late-life functioning. The resulting analysis of the combined data from over 17,500 participants aged 25–102 at baseline (including nearly 2,600 monogygotic and 4,300 dizygotic twin pairs and over 1,700 family members) aims to understand why early life adversity, and social factors such as isolation and loneliness, are associated with diverse outcomes including mortality, physical functioning (health, functional ability), and psychological functioning (well-being, cognition), particularly in later life.

Although exclusion from the workforce due to long-term sick leave (LTSL) and disability pension (DP) is a major problem in many Western countries, the etiology of LTSL and DP is not well understood. These phenomena have a strong association as most patients receiving DP have first been on LTSL. However, only a few of those on LTSL end up with DP. The present study aimed to investigate the common and specific genetic and environmental risk factors for LTSL and DP. The present study utilizes a population-based sample of 7,710 young adult twins from the Norwegian Institute of Public Health Twin Panel, which has been linked to the Historical-Event Database (FD-Trygd; 1998–2008). Univariate and bivariate twin models were fitted to determine to what degree genetic and environmental factors contribute to variation in LTSL and DP. The estimated heritabilities of LTSL and DP were 0.49 and 0.66, respectively. There was no evidence for shared environmental or sex-specific factors. The phenotypic-, genetic-, and non-familial environmental correlations between the variables were 0.86, 0.82, and 0.94, respectively. Our results indicate that familial transmission of LTSL and DP is due to genetic and not environmental factors. The risk factors contributing to LTSL and DP were mainly shared, suggesting that what increases risk for LTSL also increases risk for DP. However, a non-negligible part of the genetic variance was not shared between the variables, which may contribute to explaining why some progress from LTSL to DP, whereas others return to work.