In this article we describe the design and implementation of a database for extended twin families. The database does not focus on probands or on index twins, as this approach becomes problematic when larger multigenerational families are included, when more than one set of multiples is present within a family, or when families turn out to be part of a larger pedigree. Instead, we present an alternative approach that uses a highly flexible notion of persons and relations. The relations among the subjects in the database have a one-to-many structure, are user-definable and extendible and support arbitrarily complicated pedigrees. Some additional characteristics of the database are highlighted, such as the storage of historical data, predefined expressions for advanced queries, output facilities for individuals and relations among individuals and an easy-to-use multi-step wizard for contacting participants. This solution presents a flexible approach to accommodate pedigrees of arbitrary size, multiple biological and nonbiological relationships among participants and dynamic changes in these relations that occur over time, which can be implemented for any type of multigenerational family study.

Biochemical traits such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT) and uric acid are associated with obesity, and with risk of cardiovascular disease, metabolic syndrome and diabetes. Each is subject to genetic influences, but little is known about changes in genetic and environmental influences on these traits over time. We investigated the contribution of genetic and environmental influences to variation in these biochemical traits in adolescent twins and their nontwin siblings from 965 twin families. Twins were studied at ages 12, 14 and 16 years. Multivariate genetic models that included effects of age and sex were fitted to determine whether the same or different genetic or environmental factors influence each trait at different ages. Results showed that the genetic factors influencing AST, ALT, GGT and uric acid change over time during adolescence, and that the magnitude of these effects differs between males and females. The nonshared environment effects were generally time specific. There are developmental changes in genes affecting these traits during adolescence.

An accessory navicular bone (AN) is the most common accessory ossicle in the foot. The presence of an AN bone can trigger various foot problems, such as posterior tibial tendon pathology, flattening of the medial longitudinal arch, and medial foot pain. Despite the clinical influence of presence of an AN in foot disease, the research regarding its inheritance is still insufficient. A total of 135 pairs of monozygotic (MZ) twins, 25 pairs of dizygotic (DZ) twins, and 676 singletons from families were enrolled in order to estimate genetic influences on AN. After confirmation of zygosity and family relationship with a tandem repeat marker kit and questionnaires, the presence and type of the AN was classified through bilateral feet radiographic examination. The heritability of an AN was estimated using quantitative genetic analysis based on a variance decomposition model considering various types of family relationships: father–offspring pair, mother–offspring pair, and pooled DZ twin and sibling pairs. As a result, approximately 40.96% of the participants in this study had an AN in either foot, with type II being the most common type. The heritability for the presence of any type of an AN in any foot was estimated as 0.88 (95% CI [0.82, 0.94]) after adjusting for age and sex. Specifically, type II AN showed the highest heritability of 0.82 (95% CI [0.71–0.93]). The high heritability of an AN found in this large twin and family study suggests that an AN is determined by the substantial influence of genetic factor.

Parental adjustment following the death of a premature singleton or multiple birth infant has hitherto been studied by mailed questionnaires or telephone survey. In the present study, using an in-depth personal interview, grief reactions and adjustment patterns of nine families who lost a singleton premature infant (‘Single Group’) were compared with those of nine families who lost one of a premature multiple birth cohort (‘Multiple Group’). The interview was conducted 1–4 years after the death of the infant and evaluated specific areas or ‘scales’ of life adjustment, including individual feelings, relationship between husband and wife, and functioning at home and at work. There was no significant difference between the paternal and maternal level of adjustment of the two groups in any of the studied scales. A positive correlation was found between maternal and paternal grief reaction of the same family in the scales of individual feelings (r = 0.65), relationships between husband and wife (r = 0.70), and functioning at home (r = 0.57). Comparing the father's scale with the mother's scale revealed a significant difference only in the area of ‘individual feelings’. The gestational age, maternal bonding during hospitalisation of the infant and the parental attendance at the event of death were significantly associated with the process of parental adjustment. The results of this study support previous reports of similar parental reactions following the demise of a premature singleton or multiple birth infant. Since societal environment may not recognise the need for consolation of these families, care, compassion, and sensitivity should be encouraged in dealing with these parents at the time of their infant' death, and for a long time thereafter.

With the dramatic technological developments of genome-wide association single-nucleotide polymorphism (SNP) chips and next generation sequencing, human geneticists now have the ability to assay genetic variation at ever-rarer allele frequencies. To fully understand the impact of these rare variants on common, complex diseases, we must be able to accurately assess their statistical significance. However, it is well established that classical association tests are not appropriate for the analysis of low-frequency variation, giving spurious findings when observed counts are too few. To further our understanding of the asymptotic properties of traditional association tests, we conducted a range of simulations of a typical rare variant (~1%) under the null hypothesis and tested the allelic χ2, Cochran–Armitage trend, Wald, and Fisher's exact tests. We demonstrate that rare variation shows marked deviation from the expected distributional behavior for each test, with fewer minor alleles corresponding to a greater degree of test statistics deflation. The effect becomes more pronounced at progressively smaller α levels. We also show that the Wald test is particularly deflated at α levels consistent with genome-wide association significance, much more so than the other association tests considered. In general, these classical association tests are inappropriate for the analysis of variants for which the minor allele is observed fewer than 80 times, largely irrespective of sample size.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood disorder which occurs more often in twins than singletons. This article focuses on the psychosocial consequences of having a co-twin with ADHD. Specifically, the level of anxiety (generalized and separation) in non-ADHD children who have a co-twin with ADHD is examined using data from the Australian Twin ADHD Project (ATAP). Parental report data on 501 dizygotic (DZ) twin pairs aged 6 to 15 and their siblings were used to examine (i) anxiety symptoms in twin pairs discordant for ADHD, (ii) how the effects of an ADHD twin on their co-twin and siblings are related to the type of ADHD, and (iii) whether the effects are greater for the nonaffected twin than nontwin siblings. Results show that anxiety was high in co-twins of children with the combined subtype of ADHD, with increased symptoms of both generalized and separation anxiety. Inattentive ADHD had smaller effects, which were confined to generalized anxiety and were specific to the co-twin rather than other siblings. These results have clinical implications in managing the entire multiple birth family where one twin has ADHD, and also has implications for genetic analysis in modeling the relationship of ADHD to internalizing disorders.

Evidence for a relation between neuroticism and religion is scarce and inconsistent. The aims of the present study were to determine the association of religious upbringing with adult neuroticism scores and to examine the effect of religious upbringing on the heritability of neuroticism. As part of a longitudinal survey of twin families from the Netherlands Twin Register, data were collected on neuroticism and religious upbringing. Restricting the sample to persons aged 25 and over resulted in a sample of 4369 twins and 1304 siblings from 2698 families. Religious upbringing was significantly associated with neuroticism; in both men and women neuroticism levels were lower in those who had received a religious upbringing. There were no sex or twinsibling differences in neuroticism variances and covariances. Structural equation modeling showed differences in heritability between those with and without religious upbringing. In the group with religious upbringing, variation in neuroticism was determined for 41% by additive genetic factors and for the remaining 59% by unique environmental factors. In the group who had not received a religious upbringing, variation in neuroticism was determined for 55% by genetic factors, with evidence for both additive and nonadditive factors, and for the remaining 45% by unique environmental influences. In conclusion, having received a religious upbringing is associated with lower neuroticism scores and a lower heritability in adulthood.

Previous research has provided evidence for a genetic effect in monozygotic twinning, indicated by an increased risk for monozygotic women to have monozygotic offspring. However, since the biological mechanism for this trait is unknown, it is not clear if there exists a paternal inheritance. In this study we investigated twin pregnancies in offspring born in 1941–1996 to male twins in the Swedish Twin Registry and population controls born in 1926–1980. In total 4 225 331 offspring, of which 89 286 were twins, were studied. There was neither an increase in the probability for monozygotic men to have like-sexed twin offspring risk ratio (RR = 0.95; 95% CI = 0.77–1.13) nor an increase in the estimated number of monozygotic twin births. Thus, there is no evidence for a paternal effect on monozygotic twinning, suggesting that the gene(s) increasing the liability for division of the embryo are expressed in the mother and not in the fertilised egg.

Genetic and environmental influences on variance in phenotypic traits may be estimated with normal theory Maximum Likelihood (ML). However, when the assumption of multivariate normality is not met, this method may result in biased parameter estimates and incorrect likelihood ratio tests. We simulated multivariate normal distributed twin data under the assumption of three different genetic models. Genetic model fitting was performed in six data sets: multivariate normal data, discrete uncensored data, censored data, square root transformed censored data, normal scores of censored data, and categorical data. Estimates were obtained with normal theory ML (data sets 1–5) and with categorical data analysis (data set 6). Statistical power was examined by fitting reduced models to the data. When fitting an ACE model to censored data, an unbiased estimate of the additive genetic effect was obtained. However, the common environmental effect was underestimated and the unique environmental effect was overestimated. Transformations did not remove this bias. When fitting an ADE model, the additive genetic effect was underestimated while the dominant and unique environmental effects were overestimated. In all models, the correct parameter estimates were recovered with categorical data analysis. However, with categorical data analysis, the statistical power decreased. The analysis of L-shaped distributed data with normal theory ML results in biased parameter estimates. Unbiased parameter estimates are obtained with categorical data analysis, but the power decreases.

Twin studies of Africans have been scarce although Africans have shown the highest twin birth rate in the world. As a parallel study of the South Korean Twin Registry, the Nigerian Twin and Sibling Registry (NTSR) was developed to understand causal influences on the development of cognitive abilities, personality, and mental health among Nigerians. Currently, 1,134 twins and 404 full- and half-siblings have been registered with NTSR. This article describes research background, goals, major recruitment strategies, measures, and future directions of the NTSR.

Bread is an elementary part of the western diet, and especially rye bread is regarded as an important source of fibre. We investigated the heritability of eating bread in terms of choice of white and rye bread and use-frequency of bread in female and male twins in Denmark and Finland. The study cohorts included 575 Danish (age range 18–67 years) and 2009 Finnish (age range 22–27 years) adult twin pairs. Self-reported frequency of eating bread was obtained by food frequency questionnaires. Univariate models based on linear structural equations for twin data were used to estimate the relative magnitude of the additive genetic, shared environmental and individual environmental effects on bread eating frequency and choice of bread. The analysis of bread intake frequency demonstrated moderate heritability ranging from 37–40% in the Finnish cohort and 23–26% in the Danish cohort. The genetic influence on intake of white bread was moderate (24–31%), while the genetic influence on intake of rye bread was higher in men (41–45%) than in women (24–33%). Environmental influences shared by the twins were not significant. Consumption of bread as well as choice of bread is influenced by genetic predisposition. Environmental factors shared by the co-twins (e.g., childhood environment) seem to have no significant effects on bread consumption and preference in adulthood.

A complex interrelation exists between change in depression symptomatology and cognitive decline. Studies indicate either that depression is a direct risk factor for cognitive change over time, or vice versa. Longitudinal twin studies provide the possibility to unravel cause and effect of correlated traits. Here, we have applied twin modeling approaches to shed light on the genetic correlation between both level and change of depression symptomatology and cognitive functioning, and to further explore the bidirectionality of any such correlation using assessments of both phenotypes at two occasions 10 years apart. The study included 2,866 Danish twins with a mean age of 56.8 years at intake (range: 45–68 years). Of these, 1,267 were intact pairs. A total number of 1,582 twins (55%), of whom 557 were intact pairs, participated in the follow-up survey. We found stable cross-sectional heritability estimates of approximately 60% for general cognitive abilities and 30% for affective depressive symptoms. There was a considerable decline in the mean cognitive performance over 10 years, whereas the mean affective depression symptoms score was stable and with no genetic contribution to any individual change. Additionally, we saw a small but significant cross-trait correlation at both occasions (-0.11 and -0.09, respectively), but cross-trait cross-occasion analysis revealed no evidence that either of the two traits predicts the other over a 10-year interval. Thus, our study was not able to detect any causal association between change in depressive symptomatology and cognitive decline in middle-aged and elderly people over a 10-year interval.

Studies indicate that low birthweight (LBW) children display reduced deciduous tooth size but there is little information about permanent tooth size. It has also been shown that dental fluctuating asymmetry (FA) increases in response to various environmental influences, but the relationship between birthweight and FA remains unclear. The aim of this study was to compare tooth size and asymmetry, according to birthweight, in the deciduous and permanent dentitions of a sample of Australian twins. The study sample comprised 436 twins, classified into 2 groups: normal birthweight (NBW > 2500g) and low birthweight (LBW ≤ 2500g). For each individual it was generally possible to measure maximum mesiodistal crown diameters of both deciduous and permanent central incisors from serial dental models. Correlations were calculated between tooth-size variables and birthweight; subsequently comparisons of tooth size and FA were made between the LBW and NBW samples using Student's t tests. Small positive correlations (around .1) were noted between birthweight and tooth-size variables. There was no evidence of tooth-size reduction in the LBW male sample, but the LBW females displayed tooth-size reduction of approximately 2–3% for both deciduous and permanent incisors, compared to the NBW females. There was no evidence of increased FA in the LBW individuals of either sex. These findings indicate that developing teeth are generally well-protected from developmental disturbances during prenatal and perinatal periods. Further research is needed to clarify the biological basis of an apparently true but weak association between tooth size and birthweight.

Play among peers is an important developmental context for child socialization. We have earlier shown that children at genetic risk for aggression were more likely to be treated aggressively by unfamiliar peers during peer play, reflecting genotype-evoked behaviors manifested during play. In this study, 118 5-year-old twin pairs were paired randomly with an unfamiliar, same-age, same-sex child, thus controlling for parent- and child-chosen environments (passive and active rGE). Twins played separately from each other with unmatched children. Play behaviors were coded for aggressive and assertive behaviors. Children were also independently rated by parents for rule-breaking problem behaviors at age 5, and 97 children were rated again on these behaviors 2–10 years later. Analyses showed that children at genetic risk for early rule-breaking were more likely to have partners who behaved more aggressively, suggesting that this was evoked behavior during play. Some evidence of an ‘early bloomer’ phenomenon emerged via early difficult temperament and parent-rated delinquency significantly predicting later delinquency. Children's play, which is one of the most important influences on early development, requires further study from an rGE perspective.

Experimental studies have suggested biological factors as a possible explanation for gender disparities in perception of pain. Recently, heritability of liability to neck pain (NP) has been found to be statistically significantly larger in women compared to men. However, no studies have been conducted to determine whether the sex differences in heritability of NP are due to sex-specific genetic factors. Data on lifetime prevalence of NP from a populationbased cross-sectional survey of 33,794 Danish twins were collected and age-stratified univariate biometrical modeling using sex-limitation models was performed based on 10,605 dizygotic (DZ) twins of opposite sex to estimate the qualitative sex differences. In a full sex-limitation model the genetic component in females were higher than in males, but the genetic and the shared environmental correlations were equal to what is normally assumed between same-sex DZ twins. A ‘no-sex-effects’ model showed the overall best model fit which confirms absence of sex-related gene interaction. The age-stratified sex-limitation models showed similar results. Thus, there is no evidence for a sex-specific genetic influence in the liability of heritability of NP.

The purpose of this study was to create graphs of fundal height parameters in triplet pregnancies compared with those in twin pregnancies, and to investigate whether larger fundal heights in triplet pregnancies would predispose them to earlier delivery (before 34 weeks). The subjects were 727 twin pregnant women and 133 triplet pregnant women, who delivered after 1984. Triplet pregnancies showed significantly higher fundal heights compared with twin pregnancies at each gestational age (weeks). In triplet pregnancies, a single fundal height measurement above the 90th percentile before 34 weeks yielded a sensitivity of 31.3% and specificity of 82.4% for delivery before 34 weeks, with a positive predictive value of 50.0% and a negative predictive value of 68.0%. After adjusting for each associated factor using logistic regression, the risk of preterm labour was not significantly associated with a single fundal height measurement above the 90th percentile recorded before 34 weeks.

We explored heritabilities of the State and Trait Anxiety Inventory (STAI) and the Alcohol Use Disorders Identification Test (AUDIT), and associations including genetic and environmental correlations between the phenotypes among Korean twins and their families. We analyzed the data of 1,748 participants (835 men, 913 women, 656 individuals of monozygotic twins, 173 individuals of same-sexed dizygotic twins, 919 non-twin family members, age 30–79 years) from the Healthy Twin study. Heritabilities and bivariate analyses were assessed using the SOLAR package software. In the methods of generalized estimation equations, women in the 4th quartile of state and trait scores were 17% and 15%, respectively more likely to be hazardous alcohol users compared to women in the lower three quartiles (P < .05). However, there were no significant associations between these phenotypes in men. After adjusting for age and squared age, the heritability estimates were 0.26 in men and 0.34 in women for the state score; for the trait score, 0.35 in men and 0.31 in women; for the AUDIT score, 0.32 in men and 0.37 in women (P < .001). After adjusting for age and squared age, there was a significant genetic correlation between the trait score and the AUDIT score, and a significant non-genetic correlation between the state score and the AUDIT score in women, while there were no significant genetic or non-genetic correlations between these phenotypes in men. The STAI and AUDIT scores are heritable in Koreans and the relationships between these phenotypes may be inconsistent by sex.

Background: Our research group recently reported that aorto-radial (radial) and aorto-dorsalis-pedis (foot) pulse wave velocity (PWV) as proxies of arterial stiffness are substantially heritable in healthy youth. This article aimed at uncovering the genetic contributions of adhesion molecules, key members in the inflammatory process, to PWV in these young individuals. Methods: Radial and foot PWV were noninvasively measured with applanation tonometry in 702 black and white subjects (42% blacks, mean age 17.7 ± 3.3 years) from the Georgia Cardio vascular Twin Study. Eight functional polymorphisms from genes for E-selectin (SELE), P-selectin (SELP), intercellular adhesion molecules-1 (ICAM1), and vascular cell adhesion molecules-1 (VCAM1) were genotyped. Results: Youth with Ser290Asn or Asn290Asn genotype (SELP) compared to those with Ser290Ser had an increase in both radial and foot PWV (6.61 ± 0.07 vs. 6.41 ± 0.05 m/s, p = .026; 7.22 ± 0.05 vs. 7.04 ± 0.04 m/s, p = .007). TT homozygotes of rs2244529 (SELP) had higher foot PWV (7.28 ± 0.07 vs. 7.06 ± 0.03 m/s, p = .002) than CT heterozygotes and CC homozygotes. There appeared to be a decrease in foot PWV in youth with the 241Arg allele (ICAM1) as compared to those without (6.96 ± 0.08 vs. 7.14 ± 0.03 m/s, p = .005). For the Asp693Asp (C to T) polymorphism (VCAM1), CC genotype had higher foot PWV than CT and TT genotypes (7.18 ± 0.04 vs. 6.95 ± 0.06 m/s, p < .0001). There was an epistatic interaction between Ser290Asn, Gly241Arg, and Asp693Asp on foot PWV (p = .017), explaining 3.6% variance of the foot PWV. Conclusion: Genetic variation of adhesion molecules may be implicated in the development of arterial stiffness. Screening for adhesion molecule polymorphisms may help identify high-risk youth.

The Australian Twin Registry (ATR), established in the late 1970s, is a volunteer registry of over 30,000 pairs of Australian twins of all zygosity types and ages unselected for their health or medical history. The ATR does not undertake research itself but acts as facilitator, providing an important national and international resource for medical and scientific researchers across a broad range of disciplines. Its core functions are the maintenance of an up-to-date database containing basic contact details and baseline information, and the management of access to the resource in ways that enhance research capacity within Australia while protecting the rights of twins. The ATR has facilitated more than 200 studies using a variety of designs, including classic biometrical twin and twin family studies, co-twin control studies, intervention studies, longitudinal studies, and studies of issues relevant specifically to twins. These have yielded more than 300 peer-reviewed publications to date. Areas of major research include studies of behavior, musculoskeletal conditions, teeth and face patterns, cardiovascular risk factors, substance abuse, and risk factors for melanoma and breast cancer. Extensive longitudinal data are available for around 10,000 pairs. DNA samples have been obtained from more than 6000 twins. Considerable efforts are devoted to maintaining the commitment of registry members and recruitment. The ATR hopes to secure funding to expand its activities, including the systematic collection of DNA samples, so that it can continue to play a major role in the development of twin research and contribute to the annotation of the human genome.

Not only are alcoholism and externalizing disorders frequently comorbid, they often co-occur in families across generations; for example, paternal alcoholism predicts offspring conduct disorder just as it does offspring alcoholism. To clarify this relationship, the current study examined the ‘common genes’ hypothesis utilizing a children-of-twins research design. Participants were male monozygotic (MZ) and dizygotic (DZ) twins from the Vietnam Era Twin Registry who were concordant or discordant for alcohol dependence together with their offspring and the mothers of those offspring. All participants were conducted through a structured psychiatric interview. Offspring risk of conduct disorder was examined as a function of alcoholism genetic risk (due to paternal and co-twin alcohol dependence) and alcoholism environmental risk (due to being reared by a father with an alcohol dependence diagnosis). After controlling for potentially confounding variables, the offspring of alcohol- dependent fathers were significantly more likely to exhibit conduct disorder diagnoses than were off- spring of nonalcohol-dependent fathers, thus indicating diagnostic crossover in generational family transmission. Comparing offspring at high genetic and high environmental risk with offspring at high genetic and low environmental risk indicated that genetic factors were most likely responsible for the alcoholism–conduct disorder association. The observed diagnostic crossover (from paternal alcoholism to offspring conduct disorder) across generations in the context of both high and low environmental risk (while genetic risk remained high) supported the common genes hypothesis.