We previously described a co-twin control design using questionnaire data on monozygotic twins discordant and concordant for developmental coordination disorder (DCD) and attention deficit hyperactivity disorder (ADHD). Our results suggested that DCD and developmental ADHD had different causal pathways, and that second-born twins were at higher risk for oxygen perfusion problems than first-born twins. In the current study we further explored our findings using DNA confirmed zygosity and assessments of 4 female and 10 male sets of monozygotic twins, aged 8 to 17 years, from the first study. Using the McCarron Assessment of Neuromuscular Development (MAND), twice as many second- as first-born twins met criteria for DCD. Second-born twins attained significantly lower scores on 1-minute Apgar, MAND Gross Motor, Bimanual Dexterity and Neuromuscular Development Index. Seven of the nine twins who met criteria for DCD experienced perinatal oxygen perfusion problems. This supported findings in the first study of an association between perinatal oxygen perfusion problems and DCD, and our hypothesis that DCD and cerebral palsy have similar causal pathways. We found similar numbers of males and females discordant for DCD. On telephone interview using the Diagnostic Interview Schedule for Children Parent Interview, the only first-, and all five second-born twins who met criteria for ADHD had an inattentive component — three Inattentive; three Combined. All twins positive for ADHD were male. This adds support to our hypothesis that ADHD symptoms found in some participants may reflect secondary ADHD associated with environmental factors, rather than developmental ADHD.

It is shown that maximum likelihood estimation of variance components from twin data can be parameterized in the framework of linear mixed models. Standard statistical packages can be used to analyze univariate or multivariate data for simple models such as the ACE and CE models. Furthermore, specialized variance component estimation software that can handle pedigree data and user-defined covariance structures can be used to analyze multivariate data for simple and complex models, including those where dominance and/or QTL effects are fitted. The linear mixed model framework is particularly useful for analyzing multiple traits in extended (twin) families with a large number of random effects.

A prospective study of 692 male twins was undertaken to investigate the relationships among early adolescent problem behavior, contextual risk, and disinhibitory psychopathology. Early adolescent problem behavior was assessed by the number of the following behaviors engaged in by the time of the age-14 assessment: (1) tobacco use, (2) alcohol use, (3) marijuana use, (4) other illicit drug use, (5) sexual intercourse, and (6) police contact. Contextual risk was assessed as a composite of measures of peer models, parent-offspring conflict, and academic engagement from the age-14 assessment. Disinhibitory psychopathology was assessed by symptoms of nicotine dependence, alcohol dependence, drug dependence, and adult antisocial behavior at the age-18 assessment. Early adolescent problem behavior and contextual risk were strongly correlated (r = .53) and both were strongly and independently associated with symptoms of disinhibitory psychopathology (r from .35 to .60). The association of early adolescent problem behavior with both contextual risk and disinhibitory psychopathology was mediated entirely by genetic factors while the association between contextual risk and disinhibitory psychopathology was mediated by both genetic and nonshared environmental factors. The results are discussed in the context of emerging research on the prognostic significance of early adolescent problem behavior for risk of adult psychopathology.

The hypothesis was tested that monozygotic (MZ) and dizygotic (DZ) twins, with their lower average birth weight, have higher adult blood pressure than their singleton brothers or sisters. From the Netherlands Twin Registry, 261 twin families were recruited from a young adult and an older adult cohort with mean ages of 26.2 and 50.4 respectively. These families yielded 204 MZ twins with 71 singleton siblings and 271 DZ twins with 103 of their singleton siblings. Anti-hypertensive medication use of these 649 participants was assessed twice with a two-year interval. Resting blood pressure was measured thrice during a standardized laboratory protocol. In spite of a significant difference in birth weight (1036 gram), no differences were found in anti-hypertensive medication use at both time points between twins and singletons nor between their resting laboratory diastolic or systolic blood pressure. These results applied to each gender and to both age cohorts. Limiting the analyses to matched twin-sibling pairs of the same families and taking current weight and height into account did not change the results; no evidence was found for a twin-singleton difference. It was concluded that estimates of genetic and environmental contributions to blood pressure deriving from twin studies do not appear to be biased and may be generalized to singletons. Our results suggest that the lower birth weight in twins does not reflect the intrauterine disadvantage described by the Barker hypothesis.

Data collection for the Norwegian Cognitive NeuroGenetics sample (NCNG) was initiated in 2003 with a research grant (to Ivar Reinvang) to study cognitive aging, brain function, and genetic risk factors. The original focus was on the effects of aging (from middle age and up) and candidate genes (e.g., APOE, CHRNA4) in cross-sectional and longitudinal designs, with the cognitive and MRI-based data primarily being used for this purpose. However, as the main topic of the project broadened from cognitive aging to imaging and cognitive genetics more generally, the sample size, age range of the participants, and scope of available phenotypes and genotypes, have developed beyond the initial project. In 2009, a genome-wide association (GWA) study was undertaken, and the NCNG proper was established to study the genetics of cognitive and brain function more comprehensively. The NCNG is now controlled by the NCNG Study Group, which consists of the present authors. Prominent features of the NCNG are the adult life-span coverage of healthy participants with high-dimensional imaging, and cognitive data from a genetically homogenous sample. Another unique property is the large-scale (sample size 300–700) use of experimental cognitive tasks focusing on attention and working memory. The NCNG data is now used in numerous ongoing GWA-based studies and has contributed to several international consortia on imaging and cognitive genetics. The objective of the following presentation is to give other researchers the information necessary to evaluate possible contributions from the NCNG to various multi-sample data analyses.

We have evaluated copy number variants (CNVs) in six monozygotic twin pairs discordant for schizophrenia. The data from Affymetrix® Human SNP 6.0 arrays™ were analyzed using Affymetrix® Genotyping Console™, Partek® Genomics Suite™, PennCNV, and Golden Helix SVS™. This yielded both program-specific and overlapping results. Only CNVs called by Affymetrix Genotyping Console, Partek Genomics Suite, and PennCNV were used in further analysis. This analysis included an assessment of calls in each of the six twin pairs towards identification of unique CNVs in affected and unaffected co-twins. Real time polymerase chain reaction (PCR) experiments confirmed one CNV loss at 7q11.21 that was found in the affected patient but not in the unaffected twin. The results identified CNVs and genes that were previously implicated in mental abnormalities in four of the six twin pairs. It included PYY (twin pairs 1 and 5), EPHA3 (twin pair 3), KIAA1211L (twin pair 4), and GPR139 (twin pair 5). They represent likely candidate genes and CNVs for the discordance of four of the six monozygotic twin pairs for this heterogeneous neurodevelopmental disorder. An explanation for these differences is ontogenetic de novo events that differentiate in the monozygotic twins during development.

We aimed to determine (1) the prevalence of premenstrual syndrome in a sample of twins and (2) the relative contribution of genes and environment in premenstrual syndrome. A group of 193 subjects inclusive of same gender twins (n = 176) and females from opposite sex twin sets (n = 17) entered the study. Heritability analysis used same gender twin data only. The probandwise concordance rate for the presence or absence of premenstrual syndrome was calculated and the heritability of premenstrual syndrome was assessed by a quantitative genetic model fitting approach using MX software. The prevalence of premenstrual syndrome was 43.0% and 46.8% in monozygotic and dizygotic twins, respectively. The probandwise concordance for premenstrual syndrome was higher in monozygotic (0.81) than in dizygotic twins (0.67), indicating a strong genetic effect. Quantitative genetic modeling found that a model comprising of additive genetic (A) and unique environment (E) factors provided the best fit (A: 95%, E: 5%). No association was found between premenstrual symptom and the following variables: belonging to the opposite gender twin set, birth weight, being breast fed and vaccination. These results established a clear genetic influence in premenstrual syndrome.

The East Flanders Prospective Twin Survey (EFPTS) is a registry of multiple births in the province of East-Flanders, Belgium. It has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are ascertained at birth; basic perinatal data are recorded; chorion type and zygosity are established; and since 1969 placental biopsies have been taken and frozen at −20°C for later determination of genetic markers. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic (MZ) twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early, before the fourth day after fertilisation), the monochorionic-diamnionic pairs (intermediate, between the fourth and the seventh day post fertilisation), and the monochorionic-monoamnionic pairs (late, after the eight day post fertilisation). This added a new dimension to didymology (the science of twins; διδυμоσ= twins): the timing of twinning. Studies can be initiated on primary biases, those originating “in utero”. Such studies may throw new light on the controversy over the validity of the classic twin method, the consequences of early embryological events (before and just after implantation of the embryo), the origin of congenital malformations, the sex proportion of multiples, the gene-environment interactions as far as intrauterine environment is concerned, to name but a few.

Measuring cortisol in hair is a promising method to assess long-term alterations of the biological stress response system, and hair cortisol concentrations (HCC) may be altered in psychiatric disorders and in subjects suffering from chronic stress. However, the pattern of associations between HCC, chronic stress and mental health require clarification. Our exploratory study: (1) assessed the association between HCC and perceived stress, symptoms of depression and neuroticism, and the trait extraversion (as a control variable); and (2) made use of the twin design to estimate the genetic and environmental covariance between the variables of interest. Hair samples from 109 (74 female) subjects (age range 12–21 years, mean 15.1) including 8 monozygotic (MZ) and 21 dizygotic (DZ) twin pairs were analyzed. Perceived stress was measured with the Perceived Stress Scale and/or the Daily Life and Stressors Scale, neuroticism, and extraversion with the NEO-Five Factor Inventory or the Junior Eysenck Personality Questionnaire, and depressive symptoms with the Somatic and Psychological Health Report. We found a modest positive association between HCC and the three risk factors — perceived stress, symptoms of depression, and neuroticism (r = 0.22–0.33) — but no correlation with extraversion (-0.06). A median split revealed that the associations between HCC and risk factors were stronger (0.47–0.60) in those subjects with HCC >11.36 pg/mg. Furthermore, our results suggest that the genetic effects underlying HCC are largely shared with those that influence perceived stress, depressive symptoms, and neuroticism. These results of our proof of principle study warrant replication in a bigger sample but raise the interesting question of the direction of causation between these variables.

The negative social attributes associated with drug use and abuse/dependence may arise as a result of shared genetic or environmental factors rather than through causal pathways. To evaluate this possibility, structured interviews were conducted for 3969 male and female twins from the Mid-Atlantic Twin Registry and evaluations of their socioeconomic status (SES), social interactions, and use of drugs were obtained. Drug involvement was categorized as never used, tried, or met criteria for abuse or dependence. A co-twin control design was implemented using hierarchical linear modeling to assess whether twins who used drugs experienced lower SES and social support than non-using co-twins. Poorer social functioning in the drug-exposed twin is consistent with a causal relationship, while similar functioning in the drug exposed versus naive twins imply shared genetic or common environmental factors. Use of drugs was not significantly related to any SES measures. However, education and job status appear to share genetic influences with drug abuse/dependence. Lower income was not related to abuse/dependence of drugs. Negative interactions with friends and relatives share genetic factors with use of drugs, but the escalation from trying drugs to abusing them appears to generate discord between the abuser and friends and relatives in a causal fashion. These results indicate that presumptive causal influences of drug abuse/dependence on low SES may actually be mediated by shared genes. Drug use and social discord also appear to have shared genetic factors, but increased levels of drug involvement seem to causally influence social interactions.

It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.

Placental vascular anastomoses in twins lead to a shared circulation and may subsequently enable the development of severe complications such as twin–twin transfusion syndrome (TTTS) and twin anemia–polycythemia sequence (TAPS). The presence of vascular anastomoses has frequently and systematically been studied in monochorionic (MC) placentas, but only rarely in dichorionic (DC) placentas. The aim of this study was to compare the prevalence of vascular anastomoses and evaluate the sharing discordance in MC and DC placentas. All consecutive placentas of MC and DC twins delivered at the Leiden University Medical Center (the Netherlands) and Medical University of Warsaw (Poland) from 2012 to 2015 were routinely injected with colored dye and included in the study. We excluded twin pregnancies treated with fetoscopic laser surgery. A total of 258 placentas were analyzed in this study, including 134 MC placentas and 124 DC placentas. Vascular anastomoses were present in 99% (133/134) of MC placentas and 0% of DC placentas (p < .01). Placental share discordance between MC twins was significantly larger compared to DC twins, 19.8 (interquartile range [IQR] 8.1–33.3) and 10.8 (IQR 6.2–19.0), respectively (p < .01). Vascular anastomoses associated complications occurred in 16% (22/134) MC twins. Our findings show that vascular anastomoses are almost ubiquitous in MC placentas, but non-existent in DC placentas. In addition, unequal placental sharing appears to be more common in MC than in DC placentas.

In order to determine if twinning impacted achievement of motor milestones the attainment of early motor milestones in twins was examined and compared to published data from singletons of the same age from the same culture and birth years. We examined the influence of twinning, sex, zygosity and birth cohort (1987–2001) on the motor development of twins aged 0 to 24 months. Data on the attainment of motor milestones (turn, sit, crawl, stand and walk) of twins were collected from maternal reports. All data were corrected for gestational age. Data from the twin sample were compared to normative data from singletons, which were available from Child Health Clinics (CHC). Analyses across twin data and the CHC singleton data revealed no differences between twins and singletons in achievement of motor milestones. Girls were able to sit without support slightly earlier than boys, otherwise there were no other sex differences. Birth-order analyses revealed minimal but significant differences in turning over from back to belly and for sitting without support between the first- and second-born. Dizygotic (DZ) twins were faster than monozygotic (MZ) twins in achieving the moment of sit, crawl, stand and walk. Twins born in earlier cohorts were faster in reaching the moment of crawl, sit and walk. It is concluded that there are no differences in time of reaching motor milestones between twins and singletons within the normal range. Sex has minimal to no effect on motor development in early childhood. DZ twins achieve motor milestones sooner than MZ twins. Attainment of gross motor milestones (crawl, stand and walk) is delayed in later birth cohorts.

The Wisconsin Twin Research Program comprises multiple longitudinal studies that utilize a panel recruited from statewide birth records for the years 1989 through 2004. Our research foci are the etiology and developmental course of early emotions, temperament, childhood anxiety and impulsivity, autism, sensory over-responsivity, and related topics. A signature feature of this research program is the breadth and depth of assessment during key periods of development. The assessments include extensive home- and laboratory-based behavioral batteries, recorded sibling and caregiver interactions, structured psychiatric interviews with caregivers and adolescents, observer ratings of child behavior, child self-report, cognitive testing, neuroendocrine measures, medical records, dermatoglyphics, genotyping, and neuroimaging. Across the various studies, testing occasions occurred between 3 months and 18 years of age. Data collection for some aspects of the research program has concluded and, for other aspects, longitudinal follow-ups are in progress.

The Vietnam Era Twin Study of Aging (VETSA) is a longitudinal behavioral genetic study with a primary focus on cognitive and brain aging in men, particularly early identification of risk for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). It comprises a subset of over 1600 twins from the Vietnam Era Twin Registry. Twins live all over the USA. Assessments began when participants were in their 50s. Follow-ups were conducted every 5–6 years, and wave 3 has been completed as of this writing. The age range of participants is narrow (about 10 years). An extensive neurocognitive test battery has added precision in assessing differences in middle-aged adults, and predicting progression to MCI. Young adult cognitive test data (at an average age of 20 years) provide a means of disentangling aging effects from longstanding differences. Genome wide genotyping and plasma assays of AD biomarkers from waves 1 and 3 were conducted in wave 3. These features make the VETSA ideal for studying the heterogeneity of within-individual trajectories from midlife to old age, and for early detection of risk factors for cognitive decline.

We examine the impact of rearing by an alcoholic parent on risk for child behavior problems using data on 2492 offspring drawn from two ongoing studies of children of female and male same- and opposite-sex twin pairs. Results of regression models predicting child behavior problems from parent and co-twin lifetime history of alcohol use disorder (AUD) provide support for genetic but not environmental transmission of externalizing and a measure of total problem behaviors. Results for internalizing behavior were inconclusive with respect to transmission of risk.

Monochorionic twin pregnancies can be complicated by twin-to-twin transfusion syndrome (TTTS). The best treatment option for TTTS is fetoscopic laser coagulation of the vascular anastomoses between donor and recipient. After laser therapy, up to 33% residual anastomoses were seen. These residual anastomoses can cause twin anemia polycythemia sequence (TAPS) and recurrent TTTS. In order to reduce the number of residual anastomoses and their complications, a new technique, the Solomon technique, where the whole vascular equator will be coagulated, was introduced. The Solomon technique showed a reduction of recurrent TTS compared to the selective technique. The incidence of recurrent TTTS after the Solomon technique ranged from 0% to 3.9% compared to 5.3–8.5% after the selective technique. The incidence of TAPS after the Solomon technique ranged from 0% to 2.9% compared to 4.2–15.6% after the selective technique. The Solomon technique may improve dual survival rates ranging from 64% to 85% compared to 46–76% for the selective technique. There was no difference reported in procedure-related complications such as intrauterine infection and preterm premature rupture of membranes. The Solomon technique significantly reduced the incidence of TAPS and recurrent TTTS and may improve survival and neonatal outcome, without identifiable adverse outcome or complications; therefore, the Solomon technique is recommended for the treatment of TTTS.

The Jena Twin Registry focuses on identifying twins in eastern Germany. It is based in part on registers of multiple births and data from registration offices, and in part on a volunteer sample approached by media calls and twin clubs. The Jena Twin Study of Social Attitudes (JeTSSA) is the first study based on the Jena Twin Registry. In a sample of 226 monozygotic and 168 dizygotic adult twin pairs, self- and independent reports of significant others (peers, spouses, parents) are collected to estimate genetic and environmental effects on social attitudes and the covariation of genetic influences on personality traits and social attitudes. In addition, the effects of measured environmental variables on attitude formation are examined.

Background: Previous studies have found that child attention-deficit/hyperactivity disorder (ADHD) is associated with more parental marital problems. However, the reasons for this association are unclear. The association might be due to genetic or environmental confounds that contribute to both marital problems and ADHD. Method: Data were drawn from the Australian Twin Registry, including 1,296 individual twins, their spouses, and offspring. We studied adult twins who were discordant for offspring ADHD. Using a discordant twin pairs design, we examined the extent to which genetic and environmental confounds, as well as measured parental and offspring characteristics, explain the ADHD–marital problems association. Results: Offspring ADHD predicted parental divorce and marital conflict. The associations were also robust when comparing differentially exposed identical twins to control for unmeasured genetic and environmental factors, when controlling for measured maternal and paternal psychopathology, when restricting the sample based on timing of parental divorce and ADHD onset, and when controlling for other forms of offspring psychopathology. Each of these controls rules out alternative explanations for the association. Conclusion: The results of the current study converge with those of prior research in suggesting that factors directly associated with offspring ADHD increase parental marital problems.

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.