A new genetic factor model for multivariate phenotypic time series, iFACE, is presented which allows for the estimation of subject-specific model parameters of genetic and environmental factors. The iFACE was applied to multivariate EEG registrations obtained with single dizygotic twin pairs. The results showed evidence for considerable subject-specificity in heritabilities and environmental effects. The assumption that the population is homogeneous (i.e., that each case in the population obeys the same parametric model), does not hold for these psychophysiological data, and its use should be critically reconsidered. We conclude that the iFACE provides a powerful new methodology to assess heterogeneity (subject-specificity) based on phenotypic observations.

By definition, monozygotic (MZ) twins carry an identical set of genetic information. The observation of early post-twinning mutational events was shown to cause phenotypic discordance among MZ twin pairs. These mutational events comprise genomic alterations at different scales, ranging from single nucleotide changes to larger copy-number variations (CNVs) of varying sizes, as well as epigenetic changes. Here, we performed whole-exome sequencing (WES) in nine discordant MZ twins to identify somatic mutational events in the affected twin that might exert a dominant negative effect. Five of these MZ twin pairs were discordant for congenital heart defects (CHD), two for endocrine disorders, one for omphalocele, and one for congenital diaphragmatic hernia (CDH). Analysis of WES data from all nine MZ twin pairs using the de novo probability tool DeNovoGear detected only one apparent de novo variation in TMPRSS13 in one of the CHD-affected twins. Analysis of WES data from all nine MZ twin pairs by using standard filter criteria without the de novo probability tool DeNovoGear revealed a total of 6,657 variations in which both the twin pairs differed. After filtering for variations only present in the affected twins and absent in in-house controls, 722 variations remained. Visual inspection for read quality decreased this number to 12, present only in the affected twin. However, Sanger sequencing of the overall 13 variations failed to confirm the variation in the affected twin. These results suggest that somatic mutational events in coding regions do not seem to play a major role in the phenotypic expression of MZ discordant twin pairs.

Monochorionic twins, resulting from a single fertilized egg giving rise to two separate embryos, are monozygotic and considered genetically identical. However, discordant phenotypes have been reported in monozygotic twins. We analyzed a retrospective cohort of 155 monochorionic pregnancies (312 twins) with major discordant structural anomalies coded by the ICD-10 system in order to describe the spectrum of anomalies, the management of the pregnancies, and the perinatal outcome. Treatment options included conservative management, selective feticide with bipolar cord coagulation, or complete termination. All survivors underwent at least 24 months of postnatal follow-up. Discordancy was complicated by twin-to-twin transfusion syndrome in eight pregnancies (5%) and by selective intrauterine growth restriction in 41 (26%). Major structural anomalies affected one system in 139 cases (90%) and multiple systems in 16 (10%). Median gestational age at diagnosis was 19.1 weeks (IQR 16.4–21.3). The most frequent single-system anomalies involved the nervous and circulatory systems. In total, 72 anomalous twins (46%) and 116 normal co-twins (74%) were delivered at a median gestational age of 34.6 weeks (IQR 31.0–36.3). Neonatal/infant death of the anomalous twin occurred in 22 cases (14%), with an overall survival rate of 32% (50/155). Surviving anomalous twins underwent major surgery in 22/50 cases (44%), four of whom (8%) now suffer from severe neurologic morbidity. This study shows that a wide spectrum of major discordant structural anomalies can be found in monochorionic pregnancies. The outcome for the anomalous twin is poor, while the survival rate for the normal co-twin was 71%, with a favorable overall prognosis.

The association between birth weight and later life outcomes is of considerable interest in life-course epidemiology. Research often relies on self-reported measures of birth weight, and its validity is consequently of importance. We assessed agreement between self-reported birth weight and official birth records for Norwegian twins born 1967–1974. The intraclass correlation between self-reported birth weight and register-based birth weight was 0.91 in our final sample of 363 twins. It could be expected that 95% of self-reported birth-weight values will deviate from official records within a maximum of +446 grams and a minimum of −478 grams — around a mean deviation of 16 grams. Self-reported birth weight had a sensitivity of 0.78–0.89 and a positive predictive value of 0.59–0.85, and an overall weighted kappa of 0.71. We further assessed agreement by conducting two linear regression models where we respectively regressed self-reported birth weight and register-based birth weight on adult body mass index, a known association. The two models were not significantly different; however, there were different levels of significance in parameter estimates that warrant some caution in using self-reported birth weight. Reliability of self-reported birth weight was also assessed, based on self-reports in another sample of twins born 1935–1960 who had reported their birth weight in two questionnaires 34 years apart. The intraclass correlation was 0.86, which indicates a high degree of reliability. In conclusion, self-reported birth weight, depending on context and age when birth weight was reported, can be cautiously used.

The genetic and environmental contributions of negative valence systems (NVS) to internalizing pathways study (also referred to as the Adolescent and Young Adult Twin Study) was designed to examine varying constructs of the NVS as they relate to the development of internalizing disorders from a genetically informed perspective. The goal of this study was to evaluate genetic and environmental contributions to potential psychiatric endophenotypes that contribute to internalizing psychopathology by studying adolescent and young adult twins longitudinally over a 2-year period. This report details the sample characteristics, study design, and methodology of this study. The first wave of data collection (i.e., time 1) is complete; the 2-year follow-up (i.e., time 2) is currently underway. A total of 430 twin pairs (N = 860 individual twins; 166 monozygotic pairs; 57.2% female) and 422 parents or legal guardians participated at time 1. Twin participants completed self-report surveys and participated in experimental paradigms to assess processes within the NVS. Additionally, parents completed surveys to report on themselves and their twin children. Findings from this study will help clarify the genetic and environmental influences of the NVS and their association with internalizing risk. The goal of this line of research is to develop methods for early internalizing disorder risk detection.

For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena.

Problem behaviors are of increasing public health concern. Twin studies have revealed substantial genetic and environmental influences on children's behavior, and examining birth-weight difference could allow the identification of the specific contribution of multiple non-shared prenatal environmental factors. The Twins and Multiple Births Association Heritability Study, a UK, volunteer-based study, recruited mothers of twins aged 18 months to 5 years; 960 twins (480 pairs) were included in the analysis. Twins’ mothers answered questions relative to their pregnancy and their twins’ characteristics, and completed the Child Behavior Checklist (CBCL) 1½–5. The association between the absolute birth-weight difference and each CBCL scale's score difference was analyzed by means of multiple linear regressions. Expected mean CBCL score differences were calculated. In monozygotic (MZ) twins, statistically and clinically significant associations were found between intrapair birth-weight difference and difference in total problems, internalizing problems, and emotional reactiveness. No significant results were observed neither in dizygotic (DZ) twins when analyzed as a separate group nor in MZ and DZ twins combined. The results of the present study suggest that with increasing the absolute birth-weight difference, the intrapair difference in total problems, internalizing behaviors and emotionality increases, with smaller twins being at major risk for later behavior problems. Moreover, these results suggest a causal association between birth weight and behavior development.

Monoamniotic twinning is a rare event with an incidence of 1% of all monozygotic twins and associated with a high fetal morbidity and mortality. Confident early diagnosis is possible, but optimal management is not yet established. This article presents the experience of a single centre in managing all monoamniotic twins diagnosed during 1994–2000. Seven pairs of monoamniotic twins were identified for analysis. All were managed in accord with a unit protocol that involved early diagnosis, serial ultrasound examination and elective early delivery. In four cases, the detection of monoamnionicity was made during a first trimester nuchal scan. Discordance for structural abnormality was found in three cases where the co-twin was normal. Cord entanglement was detected antenatally in four cases. Two pairs of twins died before 20 weeks. One of these had early onset twin–twin transfusion syndrome. In five cases, the pregnancy continued beyond 20 weeks. A live birth rate of 90% and intact survival of 70% were achieved in this group. We believe that ultrasound is reliable in diagnosing monoamniotic twins and the detection of cord entanglement. Timing of elective delivery is a balance between the risks of preterm birth at a specific gestational age in an individual centre compared with the unquantifiable risks of fetal death if an expectant policy were pursued. The decision to deliver and at which gestational age should combine input from the parents, neonatologist, fetal medicine consultant and the obstetrician.

The purpose of this study was to examine the genetic contribution to handedness and footedness in childhood using one of the largest available databases of Japanese twins. The participants were 1131 twin pairs, 1057 males and 1205 females, of 11 or 12 years of age (6th grade of secondary school in the Japanese education system). All data were gathered by questionnaire. The prevalence of left (nonright) handedness was 15% in males and 13% in females. The prevalence of left (nonright) footedness was 13% in males and 11% in females. The similarities between twin pairs, estimated by concordance rates and tetrachoric correlations, suggested a slight genetic effect on male handedness, no genetic effect on female handedness, and no genetic effect on footedness in either sex. Structural equation modeling showed small genetic factors (11%) in male handedness and no genetic factors in female handedness. As to footedness, no genetic factors were observed in either sex. The effects of nonshared environmental factors were large (85%) in males and moderate (44%) in females. Moreover, handedness and footedness tended to be concordant irrespective of sex, with polychoric correlations over r = .70. The results of bivariate genetic analyses were not necessarily satisfactory. For males, no model fit. For females, shared and nonshared environmental factors explained the concordance of handedness and footedness. It was concluded that the genetic effects on handedness and footedness are relatively small, as is their association; moreover, considerably large twin samples are needed to obtain stable and appropriate results.

Recent successes in identifying the underlying genetic mechanisms for neurological diseases, particularly for their Mendelian forms, have had profound implications for their diagnostics, treatment and classification. However, there has never been an attempt to compare familial risks in a systematic way among and between the main neurological diseases. Familial risks were here defined for siblings who were hospitalized because of a neurological disease in Sweden. A nationwide database for neurological diseases was constructed by linking the Multigeneration Register of 0- to 69-year-old siblings to the Hospital Discharge Register for the years 1987 to 2001. Standardized risk ratios were calculated for affected sibling pairs by comparing them to those whose siblings had no neurological disease. There were three main results. First, it was shown that all disease groups had a familial risk, with the exception of transient ischemic attacks, and the risks could be ranked from the highest (3451) for Huntington's disease to the lowest (2.1) for inflammatory diseases. Second, increased familial risks were shown for disease subtypes for which susceptibility genes or familial clustering have not been demonstrated previously, including multiple sclerosis, sleep apnea, nerve, nerve root and plexus disorders, and cerebral palsy. Third, based on the available sample size there was no convincing evidence for familial comorbidity between the disease groups, suggesting that the factors causing familial aggregation, probably usually heritable genes, are distinct for each subtype. The high familial risks for neurological disease imply heritable etiology and opportunities for identification of further susceptibility genes.

Recently, there has been a significant increase in the rate of multiple births in most developed countries. However, few population-based studies have been conducted in China regarding the epidemiology of twin births in recent years. We performed a descriptive analysis of twin births from 1993 to 2005 using data from a population-based perinatal care program in southeast China. The twin birth rate in southeast China was 0.65%, and the twin birth rates from 1993 to 2005 fluctuated between 0.60% and 0.70%. During the three periods of 1993–1996, 1997–2000, and 2001–2005, the twin birth rate increased from 0.57% to 0.71% in urban areas (p = .005) and from 0.59% to 0.68% in mothers who had an education level of high school or higher (p = .046). After 2000, the twin birth rate of primiparae 30 years of age and older significantly increased from 0.72% to greater than 1.20%. We concluded that the twin birth rates in southeast China from 1993 to 2005 stayed constant in the overall population but increased in certain subgroups of women, presumably due to increased use of fertility treatment and the development of assisted reproductive technology.

Phenotypically discordant monozygotic twins offer the possibility of gene discovery through delineation of molecular abnormalities in one member of the twin pair. One proposed mechanism of discordance is postzygotically occurring genomic alterations resulting from mitotic recombination and other somatic changes. Detection of altered genomic fragments can reveal candidate gene loci that can be verified through additional analyses. We investigated this hypothesis using array comparative genomic hybridization; the 50K and 250K Affymetrix GeneChip® SNP arrays and an Illumina custom array consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events and small aberrations beyond the detection level of our experimental approach cannot be ruled out. The stability of genomes we observed in our study samples also suggests that detection of discordant events in other monozygotic twin pairs would be remarkable and of potential disease significance.

This paper describes the creation of a unique maternal identifier for use in the investigation of perinatal, postneonatal and child outcomes in relation to maternal characteristics. All Midwives’ records of Western Australian (WA) births were routinely linked to registrations of births and deaths for infants born from 1980 to 1992 inclusive, then linked to WA hospital discharge data and to registries of birth defects and cerebral palsy to create a longitudinal health record for each infant. However, since each birth to a woman was recorded as a separate event, there was no way to identify siblings. Probabilistic record linkage, based on information about the mother, was used for this task. Logical inconsistencies within the data were used to test the validity of the linkages between birth records attributed to each mother. Information about the mother from other epidemiological studies and data abstracted from hospital case notes was also used to validate sibships. Linkage of the records of 310,255 births in WA during that period resulted in the formation of 181,133 sibships of one or more children. Pooling the results of all of the validation methods gave an error of 0.9%. Linkage identified 3678 sibships containing multiple births, and 305 sets of maternal twins. Ascertainment of twins and their siblings for an ongoing twin register, the WA Twin Child Health (WATCH) study, was a natural consequence of this process.

The study of twins and their families provides a highly useful tool for disentangling the genetic and environmental origins of traits. The Cardiff Study of All Wales and North West of England Twins (CaStANET) has followed children and adolescents over time into early adulthood, assessing a wide range of aspects of behavior and psychopathology using self-, parent and teacher reports. Four main waves of data collection have taken place to date, which have provided a wealth of information on the contributions of genetic and environmental risk factors to the psychological health of young people. This article first describes the CaStANET register and subsequently presents some of the findings that have emerged from this resource, with a focus on depression and anxiety, chronic fatigue, attention-deficit/hyperactivity disorder, conduct problems and prosocial behavior. We describe in somewhat more detail the 4th wave of data collection, which has recently been completed and has provided us with extensive information on substance use and problem use as well as associated risk factors in the twins and their families, including longitudinal data on conduct problems and the relations between family members. Because of the wealth of data already collected and the opportunity for genetically informative analyses over time, CaStANET provides a valuable resource for understanding the complexities of the psychological development of young people.

Mexican Americans (MAs) and American Indians (AIs) constitute conspicuously understudied groups with respect to risk for post-traumatic stress disorder (PTSD), especially in light of findings showing racial/ethnic differences in trauma exposure and risk for PTSD. The purpose of this study was to examine genetic influences on PTSD in two minority cohorts. A genome-wide association study (GWAS) with sum PTSD symptoms for trauma-exposed subjects was run in each cohort. Six highly correlated variants in olfactory receptor family 11 subfamily L member 1 (OR11L1) were suggestively associated with PTSD in the MA cohort. These associations remained suggestively significant after permutation testing. A signal in a nearby olfactory receptor on chromosome 1, olfactory receptor family 2 subfamily L member 13 (OR2L13), tagged by rs151319968, was nominally associated with PTSD in the AI sample. Although no variants were significantly associated after correction for multiple testing in a meta-analysis of the two cohorts, pathway analysis of the top hits showed an enrichment cluster of terms related to sensory transduction, olfactory receptor activity, G-protein coupled receptors, and membrane. As previous studies have proposed a role for olfaction in PTSD, our results indicate this influence may be partially driven by genetic variation in the olfactory system.

There has been much interest in evidence that people with lower birthweight have higher risk of adult cardiovascular disease, but the causal pathways underlying such observations are uncertain. Study of twins offers an opportunity to shed light on these pathways, in three different ways. First, in a twin pregnancy maternal nutritional resources and the “supply line” to the fetuses will be more “stretched”. We hypothesise that study of twin pregnancies is a more efficient way to identify modifiable maternal factors that influence later health than studies of singleton pregnancies. Second, twins have lower birthweight than singletons. Comparison of cardiovascular disease risk in twins versus that in singletons will provide insight into whether birthweight per se is in the underlying causal pathway of interest, and whether factors constraining fetal growth of twins (versus singletons) affect later outcome. Third, twin cohorts provide an opportunity to investigate the role of “shared” factors versus factors affecting each individual fetus, by comparing results of within-cohort versus within-pair analyses. Generalisability of findings in twins is debated. We suggest that findings in monochorionic twins (or in the absence of chorionicity data, those from monozygotic twins) need to be interpreted with caution.

The aim of this study was to determine the influence of genetic factors on the first episode of acute myocardial infarction. Probandwise concordances, tetrachoric correlations and quantitative genetic analyses of liability were applied to data drawn from the Swedish Twin Registry and the Swedish Acute Myocardial Infarction Register. All same-sexed twin pairs born between 1886 and 1958 who were alive in 1987 were included in the analyses. Our results show that concordance rates for acute myocardial infarction in monozygotic (MZ) twins were similar across sexes (among males .26 and females .27). For dizygotic (DZ) twins the concordances were .20 for males and .16 for females, yielding a greater MZ–DZ concordance differential for females than males. Tetrachoric correlations were greater for MZ than DZ twins for both sexes (.49 for male MZ and .34 for male DZ-twins and .56 and .35 for female MZ and DZ twins respectively). Quantitative genetic analyses of liability resulted in equal variance components for males and females (.36) but significantly different thresholds (prevalences). In conclusion, liability to first occurrence of acute myocardial infarction is moderately influenced by genetic variants in both sexes. The familial influence on phenotypic variance is exclusively explained by additive genetic factors.

The Arizona Twin Project is an ongoing longitudinal study designed to elucidate gene–environment interplay underlying the development of risk and resilience to common mental and physical health problems during infancy, childhood and adolescence. Specificity of risk is carefully examined across mental and physical health and how these influences vary across socioeconomic and sociocultural environments. Participants are a sample of approximately 700 twins (31% Latinx) recruited from birth records in the state of Arizona, USA. Twins are 32% monozygotic twins, 36% same-sex dizygotic (DZ), 32% opposite-sex DZ, currently 10–11 years of age. Primary caregivers were interviewed on twins’ development and early physical and social environments when twins were 1, 2 and 5 years of age. In-depth objective measurement commenced in middle childhood, with in-person assessments at 8–11 years of age, with plans to continue to follow the sample across adolescence. Middle childhood measures focus on children’s physical and mental health, including diurnal cortisol, actigraphy-based measures of sleep and activity, cold pressor task assessing acute pain, and reaction time tasks assessing executive functioning. Preliminary findings illustrate that objective assessments of children’s health are highly heritable, but they do not always share genetic etiology with more commonly used subjective assessments. Exposure to early adversity moderates genetic influences on both executive functioning and health, with higher heritability typically seen under adverse conditions. Future directions include an examination of how pubertal stage affects genetic and environmental influences on diurnal cortisol, sleep, chronic pain, and mental health.

Since established in 1998, the Keio Twin Project (KTP) has been dedicated to investigating genetic and environmental sources contributing to human psychological traits in adolescence and young adulthood. A population-based twin registry was constructed by the KTP through the use of official residential records in the Tokyo area, and to date requests to participate in our research have generated 1040 pairs of twins and triplets of age 14 to 30, forming one of the largest twin registries in Asia. Our comprehensive datasets, obtained through questionnaires, performance tests, and physical measurements, cover a wide range of human traits: personality, psychiatry, mental health, sociality, cognition, and physical index. Demographic variables and environment of upbringing are also sought by twins and by some parents. This extensive information allows us to clarify the genetic and environmental overlap across multiple traits as well as specificities unique to single traits. Adding an evolutionary psychology perspective to the behavior genetics framework is currently being attempted in order to develop a grand theory of human genetics.

Attitudes towards foreign policy have typically been explained by ideological and demographic factors. We approach this study from a different perspective and ex amine the extent to which foreign policy preferences correspond to genetic variation. Using data from the Minnesota Twin Family Study, we show that a moderate share of individual differences in the degree to which one's foreign policy preferences are hawkish or dovish can be attributed to genetic variation. We also show, based on a bivariate twin model, that foreign policy preferences share a common genetic source of variation with political ideology. This result presents the possibility that ideology may be the causal pathway through which genes affect foreign policy preferences.