Temporal variations in the stillbirth rate among singletons, twins and triplets in Sweden between 1869 and 1967 were studied. Both among single and multiple births there were marked secular decreasing trends in the stillbirth rates. Based on our long time series since 1869, this study confirms that among twins and triplets the stillbirth rate was higher among same-sexed than among opposite-sexed sets. Comparisons between the stillbirth rates among twin births in urban and rural regions indicate higher stillbirth rates in rural areas. In addition, the stillbirth rates among twins of unmarried mothers were higher than those of twins of married mothers. These findings also hold for both same-sexed and opposite-sexed twin pairs. Analyses of the stillbirth rates for singletons and for different types of twins indicate that up to 1950 the risk of stillbirth among males was almost constantly between 15% to 20% higher than among females. After that the difference in the risk decreased. Comparisons with other populations were performed.

Twins traditionally retain a special status in many African societies. In Guinea-Bissau, twins are often well regarded yet still suffer from a very high mortality, especially in the perinatal and infant period. At the Bandim Health Project, a health and demographic surveillance site, we have recently established one of the first twin registries in Sub-Saharan Africa. Our short-term aim is to describe twin mortality and morbidity in order to design appropriate health interventions. Our long-term goal is a large-scale database to explore the pathogenesis of prevalent diseases; for example, diabetes mellitus, metabolic syndrome, and infectious diseases such as HIV, tuberculosis, and malaria. A major focus area is also the etiology of low birth weight and how epigenetic processes might modulate the consequences of low birth weight in Sub-Saharan Africa. For this, monozygotic twin studies represent a powerful tool. Though twin studies have been carried out by the Bandim Health Project for more than 30 years, the renewed registry described here was officially established in 2009 and includes both a cohort of newborn twins and a cohort of young and adult twins. Currently more than 1,500 twins are being followed in the two cohorts combined. We believe that the registry holds exciting possibilities and will encourage the establishment of further twin registries across the region.

The Barker hypothesis states that low birth weight (BW) is associated with higher risk of adult onset diseases, including mental disorders like schizophrenia, major depressive disorder (MDD), and attention deficit hyperactivity disorder (ADHD). The main criticism of this hypothesis is that evidence for it comes from observational studies. Specifically, observational evidence does not suffice for inferring causality, because the associations might reflect the effects of confounders. Mendelian randomization (MR) — a novel method that tests causality on the basis of genetic data — creates the unprecedented opportunity to probe the causality in the association between BW and mental disorders in observation studies. We used MR and summary statistics from recent large genome-wide association studies to test whether the association between BW and MDD, schizophrenia and ADHD is causal. We employed the inverse variance weighted (IVW) method in conjunction with several other approaches that are robust to possible assumption violations. MR-Egger was used to rule out horizontal pleiotropy. IVW showed that the association between BW and MDD, schizophrenia and ADHD is not causal (all p > .05). The results of all the other MR methods were similar and highly consistent. MR-Egger provided no evidence for pleiotropic effects biasing the estimates of the effects of BW on MDD (intercept = -0.004, SE = 0.005, p = .372), schizophrenia (intercept = 0.003, SE = 0.01, p = .769), or ADHD (intercept = 0.009, SE = 0.01, p = .357). Based on the current evidence, we refute the Barker hypothesis concerning the fetal origins of adult mental disorders. The discrepancy between our results and the results from observational studies may be explained by the effects of confounders in the observational studies, or by the existence of a small causal effect not detected in our study due to weak instruments. Our power analyses suggested that the upper bound for a potential causal effect of BW on mental disorders would likely not exceed an odds ratio of 1.2.

This article reviews the Southern Illinois Twins/Triplets and Siblings Study (SITSS) and describes some of the findings related to recent projects that were completed using this sample. At this time, the SITSS has enrolled 375 twin pairs, 12 triplet families, 1 family of quadruplets, 98 nontwin sibling pairs and 287 singletons. Testing begins for twins and triplets as young as age 1 and then occurs yearly on their birthdays until 5 years of age. Through age 20, various follow-up studies have been conducted on the SITSS sample to examine their social, emotional, and cognitive development across childhood and adolescence from a behavioral genetic perspective. A variety of methodologies have been used to investigate gene–environment correlations (rGE) and gene–environment interactions (GxE). Advanced statistical procedures (e.g., genetic likelihood indices and multilevel modeling) have been utilized to further investigate genetic underpinnings of behavior. Recent results have indicated genetic influences on the aggressiveness of preschoolers’ media preferences, increased problem behaviors related to young children’s overestimation of self-competence, and the influence of early life temperament and internalizing problems on adolescent health behaviors. Additionally, the SITSS has provided evidence for evocative rGE for various behaviors (aggression, prosocial and play), as well as findings supporting interactions between the dopamine receptor D4 gene (DRD4) and the environment (peer victimization, prenatal birth complications and parental sensitivity). Together, by use of multitrait and multimethodological investigations, this behavior genetic data set assists in furthering our understanding of biological and environmental influences on children’s development.

This article analyzes the contribution of genetics and the environment to educational attainment, occupational status, and income using data from over 1,100 monozygotic and 400 dizygotic Australian twin pairs aged from 18 to 99. The respective heritability estimates were 0.54, 0.37, and 0.18. The bivariate heritabilities were 0.71 for educational attainment and occupational status, 0.37 for education and income, and 0.61 for occupational status and income. There were no gender and cohort differences in the heritabilities for education and occupation, but for income, contrary to expectations, the heritabilities were significantly higher among women and for the older cohort (aged 50 or older). The sizable contribution of genes to these socioeconomic outcomes suggests that standard sociological and economic theories on the socioeconomic career require substantial modification to accommodate the role of genetics.

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproduction techniques using in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI). Its etiology has still not yet been fully resolved. Human chorionic gonadotrophin, administered exogenously as well as produced endogenously during pregnancy, is responsible for the onset of OHSS, and high levels of estradiol appear to worsen the condition. In this case series, the course of mild to severe OHSS was evaluated in 19 intact twin pregnancies after IVF/ICSI. Another serious complication associated with OHSS is thromboembolic events. In these cases, the pregnancy can be protected through anticoagulation treatment, but there may be exceptions to this. This series includes a case of bilateral thrombosis of the internal and external jugular veins in the 7th gestational week in a twin pregnancy after OHSS and ICSI, with termination of the pregnancy in the 9th gestational week due to progressive thrombosis during anticoagulation therapy.

This study aimed to evaluate the prevalence of birth-weight discordance among twins, to determine the risk cut-off point for birthweight discordance, and to clarify whether perinatal deaths are aggravated by birthweight discordance or by low birthweight itself. A population-based analysis of all twins born between 1995 and 1999 in Japan was conducted using data collected from national birth, death and stillbirth certificates. Birthweight discordance was determined as: higher birthweight minus lower birthweight divided by higher birthweight multiplied by 100. Among twins with a birthweight discordance of more than 15%, the fetal and perinatal mortality rate was higher than that of twins with a discordance of less than 15%. Ninety per cent of the relative cumulative frequency of twin live-births were within 25% of the birthweight discordance. Logistic regression analysis showed that the stillbirth of at least one of the twins is associated with the birthweight of the larger twin and birthweight discordance. It also showed that the stillbirth of both twins in the twin pair is associated with the birth-weight of larger twins and the gestational weeks. It was clarified that birthweight discordance was associated with the stillbirth of only one twin in the twin pair, and the stillbirth of both twins in the twin pair was associated with low birthweight itself.

Project TALENT is a US national longitudinal study of about 377,000 individuals born in 1942–1946, first assessed in 1960. Students in about 1,200 schools participated in a 2-day battery covering aptitudes, abilities, interests, and individual and family characteristics (Flanagan, 1962; www.projectTALENT.org). Follow-up assessments 1, 5, and 11 years later assessed educational and occupational outcomes. The sample includes approximately 92,000 siblings from 40,000 families, including 2,500 twin pairs and 1,200 other siblings of twins. Until recently, almost no behavior genetic research has been conducted with the sample. In the original data collection information was not collected with the intent to link family members. Recently, we developed algorithms using names, addresses, birthdates, and information about family structure to link siblings and identify twins. We are testing several methods to determine zygosity, including use of yearbook photographs. In this paper, we summarize the design and measures in Project TALENT, describe the Twin and Sibling sample, and present our twin-sib-classmate model. In most twin and family designs, the ‘shared environment’ includes factors specific to the family combined with between-family differences associated with macro-level variables such as socioeconomic status. The school-based sampling design used in Project TALENT provides a unique opportunity to partition the shared environment into variation shared by siblings, specific to twins, and associated with school- and community-level factors. The availability of many measured characteristics on the family, schools, and neighborhoods enhances the ability to study the impact of specific factors on behavioral variation.

CDKN1C and KCNQ1OT1 are imprinted genes that might be potential regulators of placental development. This study investigated placental expressions of CDKN1C and KCNQ1OT1 in monozygotic twins with and without selective intrauterine growth restriction (sIUGR). Seventeen sIUGR and fifteen normal monozygotic(MZ) twin pairs were examined. Placental mRNA expressions of CDKN1C and KCNQ1OT1 were detected by real-time fluorescent quantitative PCR. CDKN1C protein expression was detected by immunohistochemical assay and Western-blotting. In the sIUGR group, smaller fetuses had a smaller share of the placenta, and CDKN1C protein expression was significantly increased while KCNQ1OT1 mRNA expression was significantly decreased. The CDKN1C/KCNQ1OT1 mRNA ratio was lower in the larger fetus than in the smaller fetus (p < .05). In the control group, CDKN1C protein expression showed no difference between larger and smaller fetuses, while KCNQ1OT1 mRNA expression was significantly lower in the larger fetus, and the CDKN1C/KCNQ1OT1 mRNA ratio was higher in the larger fetus than in the smaller fetus (p < .05). Our findings showed that pathogenesis of sIUGR may be related to the co-effect of the up-regulated protein expression of CDKN1C and down-regulated mRNA expression of KCNQ1OT1 in the placenta.

One way to achieve the large sample sizes required for genetic studies of complex traits is to combine samples collected by different groups. It is not often clear, however, whether this practice is reasonable from a genetic perspective. To assess the comparability of samples from the Australian and the Netherlands twin studies, we estimated Fst (the proportion of total genetic variability attributable to genetic differences between cohorts) based on 359 short tandem repeat polymorphisms in 1068 individuals. Fst was estimated to be 0.30% between the Australian and the Netherlands cohorts, a smaller value than between many European groups. We conclude that it is reasonable to combine the Australian and the Netherlands samples for joint genetic analyses.

Models are presented for the analysis of longitudinal data from same-age twins which permit the exploration of a remarkably diverse array of alternative explanations for continuity and change during development. Data of this type permit the detection of new sources of genetic or environmental covariation during development that are not expressed at earlier ages and, because they include the effects of age-specific genes, the resulting heritability estimates are more reliable than those obtained from relatives who differ in age. The proposed models were applied to measurements of HDL cholesterol obtained on 81 pairs of monozygotic (MZ) twins and 69 dizygotic (DZ) pairs at 11, 12.5 and 14 years of age. All three MZ co-twin correlations were substantially higher than the self correlations across occasions, suggesting that new sources of genetic or environmental covariation must be expressed during early adolescence. This interpretation was confirmed by analysis of the full covariance matrices which showed that only models which assumed the expression of new or age-specific genes could explain the observed pattern of covariation. Because they include the effects of age-specific genes, the resulting heritabilities (0.80–0.83) were substantially higher than many previous estimates.

Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p < .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.

The phenotypic (observed), genetic, and environmental correlations were examined in a sample of adult twins between the four factors and global score of the trait emotional intelligence questionnaire (TEIQue) and the seven vocational interest factors of the Jackson Career Explorer (JCE). Multiple significant correlations were found involving the work style vocational interest factor (consisting of job security, stamina, accountability, planfulness, and interpersonal confidence) and the social vocational interest factor (which included interests in the social sciences, personal services, teaching, social services, and elementary education), both of which correlated significantly with all of the TEIQue variables (well-being, self-control, emotionality, sociability, and global trait EI). Following bivariate genetic analyses, most of the significant phenotypic correlations were found to also have significant genetic correlations as well as significant non-shared (unique) environmental correlations.

Background: Previous research indicates that liability to disability pension (DP) due to mental diagnoses is moderately influenced by genetic factors. This study investigates whether genetic contributions to the liability to DP due to mood and neurotic diagnoses overlap with the genetic influences on major depression (MD), generalized anxiety disorder (GAD), or chronic fatigue (CF).

Method: A prospective cohort study including 9,985 female twins born in Sweden 1933–1958. The presence of MD, GAD, and CF was assessed by computer-assisted telephone interviews conducted in 1998–2002. Data on DP due to mood and neurotic diagnoses were obtained from nationwide registers for the years 1998–2010. Common genetic and environmental influences on the phenotypes were estimated by applying structural equation modeling.

Results: The prevalence of MD/GAD was 30%, CF 8%, and DP due to mood and neurotic diagnoses 3% in 2010. Genetic effects on MD/GAD explained 31% of the total genetic variation in DP, whereas genetic contributions in common with CF were small and not significant. The majority of the total non-shared environmental variance in DP (85%) was explained by the factors that were unique to DP.

Conclusions: Large proportions of genetic and non-shared environmental influences in DP due to mood and neurotic diagnoses were not explained by the contributions from MD/GAD or CF. The results suggest that the process leading to DP is complex and influenced by factors other than those related to the disorder underlying DP.

Several studies report apparent sibling contrast effects in analyses of twin resemblance. In the presence of genetic differences, contrast effects reduce the dizygotic (DZ) twin correlation relative to that in monozygotic (MZ) twins and produce higher DZ than MZ variance. Explanations of contrast effects are typically cast in terms of direct social interaction between twins or an artifact of the process of rating children by their parents. We outline a model for sibling imitation and contrast effects that depends on social interaction between parents and children. In addition to predicting the observed pattern of twin variances and covariances, the parental mediation of child imitation and contrast effects leads to differences in the variance of parents of MZ and DZ twins and differences between the correlations of parents with their MZ and DZ children.

Genetic predispositions play an important role in the development of internalizing and externalizing behaviors. Understanding the mechanisms through which genetic risk unfolds to influence these developmental outcomes is critical for developing prevention and intervention efforts, capturing key elements of Irv's research agenda and scientific legacy. In this study, we examined the role of parenting and personality in mediating the effect of genetic risk on adolescents’ major depressive disorder and conduct disorder symptoms. Longitudinal data were drawn from a sample of 709 European American adolescents and their mothers from the Collaborative Studies on Genetics of Alcoholism. Results from multivariate path analysis indicated that adolescents’ depressive symptoms genome-wide polygenic scores (DS_GPS) predicted lower parental knowledge, which in turn was associated with more subsequent major depressive disorder and conduct disorder symptoms. Adolescents’ DS_GPS also had indirect effects on these outcomes via personality, with a mediating effect via agreeableness but not via other dimensions of personality. Findings revealed that the pattern of associations was similar across adolescent gender. Our findings emphasize the important role of evocative gene–environment correlation processes and intermediate phenotypes in the pathways of risk from genetic predispositions to complex adolescent outcomes.

High-resolution genomic tests have the potential to revolutionize healthcare by vastly improving mutation detection. The use of chromosomal microarray (CMA) represents one of the earliest examples of these new genomic tests being introduced and disseminated in the clinic. While CMA has clear advantages over traditional karyotyping in terms of mutation detection, little research has investigated the process by which CMA was implemented in clinical settings. Fifteen key informants, six clinicians, and nine laboratory scientists from four Australian states were interviewed about their experiences during and in the time since CMA was adopted for clinical use. Participants discussed challenges such as result interpretation and communication. Strengths were also highlighted, including the collaborative approaches of some centers. Clinical experiences and opinions can inform larger studies with a range of stakeholders, including patients. The historical perspectives from this retrospective study can be helpful in guiding the implementation of future genomic technologies such as whole exome/genome sequencing.

This study investigates the degree to which internalizing disorders (anxiety and mood disorders) are prospectively associated with sick leave granted for mental and somatic disorders, and the extent to which common genetic and environmental risk factors influence these relationships. Data include self-reported symptoms of psychological distress from 7,598 young adult twins and diagnostic interviews on a subsample of 2,766 adult twins, subsequently linked to registry data on sick leave. Regression analyses and multivariate twin models were used to investigate the relationship between internalizing disorders and sick leave. Internalizing disorders were associated with sick leave granted for both mental disorders and somatic disorders. The association between internalizing disorders and sick leave granted for mental disorders was influenced by genetic and non-shared environmental factors, while the association between internalizing disorders and sick leave granted for somatic disorders could be explained by common genetic factors alone. Monozygotic twins discordant for internalizing disorders differed significantly in rates of sick leave granted for mental but not somatic disorders. In conclusion, internalizing disorders in young adults predict sick leave granted for both mental and somatic disorders. Environmental risk factors for internalizing disorders seem to influence sick leave granted for mental disorders, but not sick leave granted for somatic disorders.

Good nutrition is central to achieving optimal fetal growth and development, and to maintaining maternal health and wellbeing. For multiple pregnancies, there is a growing body of evidence linking good maternal nutrition and weight gain to positive perinatal outcomes including reduced incidence of low birthweight and very low birthweight infants. Nutrition intervention appears to have important clinical implications for infant morbidity and mortality. Nutritional counselling can help women improve and maximise their intake of “at risk nutrients” such as iron, folate, essential fatty acids, calcium and ensure adequate energy intake to meet weight gain targets. Recommended optimal weight gains range from 16–20kg for twin pregnancies. Expert dietetic guidance is often warranted, especially for women expecting triplets or quadruplets.

Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.