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.

Objective: A recent Children-of-Female-Twin design suggests that the association between maternal alcohol use disorder and offspring ADHD is due to a combination of genetic and environmental factors, such as prenatal nicotine exposure. We present here a complementary analysis using a Children-of-Male-Twin design examining the association between paternal alcoholism and offspring attention deficit hyperactivity problems (ADHP). Methods: Children-of-twins design: offspring were classified into 4 groups of varying genetic and environmental risk based on father and co-twin's alcohol dependence status. Results: Univariate results are suggestive of a genetic association between paternal alcohol dependence and broadly defined offspring ADHP. Specifically, offspring of male twins with a history of DSM-III-R alcohol dependence, as well as offspring of non-alcohol dependent monozygotic twins whose co-twin was alcohol dependent, were significantly more likely to exhibit ADHP than control offspring. However, multivariate models show maternal variables independently predicting increased risk for offspring ADHP and significantly decreased support for a genetic mechanism of parent-to-child transmission. Conclusions: In support of earlier work, maternal variables (i.e., maternal ADHD and prenatal exposure) were strongly associated with child ADHP; however, the role of paternal alcohol dependence influences was not definitive. While genetic transmission may be important, the association between paternal alcohol dependence and child ADHP is more likely to be indirect and a result of several pathways.

Two major challenges to conducting a community-based twin study of pathological gambling (PG) disorder are that: (a) it is relatively rare, and (b) individuals with the disorder in the community may be difficult to locate and recruit. We describe a new study of 4,764 individuals recruited from the Australian Twin Registry in which we attempt to effectively deal with the first challenge and examine the impact of the second challenge. The lifetime prevalence of DSM-IV PG in this Australian twin sample was 2.2%, which is 400–500% higher than has been obtained in prevalence surveys conducted in the United States. A number of predictors of non-participation were identified, including a lifetime PG disorder diagnosis, but these did not have a large net effect on the estimated number of individuals with PG or related characteristics in the twin sample. Results of biometric modeling suggested that the effect of genetic, shared family environmental, and nonshared environmental influences on the propensity to engage in 11 different specific forms of gambling (e.g., playing the lottery, betting on horse or dog races, playing electronic gaming machines) were generally moderate, low, and moderate, respectively, with mean parameter estimates obtained of 43%, 10%, and 46%. An intriguing comparison with results from a 1963 US adolescent twin study conducted by Loehlin and Nichols (1976) suggests that: (a) propensity genes for gambling involvement may be more likely to be expressed in the heavy-gambling Australian culture, or that (b) the family environment has a transient effect on the gambling behavior of young people.

Fifty-two Australian couples who had experienced the death of at least one member of a multiple birth (twin or higher order), with at least one survivor of that birth, were interviewed about their experiences at the time of the death, and since. This study compared parents' coping after the twins' deaths using the Beck Depression Inventory II, Perinatal Grief Scale, and unstructured interviews with some structured queries. Parents provided information on the influence of family, community and medical staff. According to retrospective reports, mothers experienced significantly more depression and grief than fathers at the time of loss. Both parents found the death of their twins grievous, but fathers, unlike mothers, were not encouraged to express their emotions. Although parents generally agreed about what helped them cope, fathers believed that they should be able to cope regardless of their grief. The strength of parents' spiritual beliefs had increased significantly since their loss, and there was some evidence that depressed and grieving mothers turned to spiritual support. Parents whose children died earlier reported levels of depression similar to those reported by parents whose children died later. To date, this is the largest study of grief in couples who have experienced the death of a twin and who have a surviving twin or higher order multiple.

The associations between social support and depression, and between stress and depression have been the subject of considerable research, and although this has included longitudinal designs, these have rarely controlled for genetic effects that mediate these associations. The sample comprised 7,356 female and 4,882 male participants aged 18–95 from the Australian NHMRC Twin Registry (ATR). Of these, between 100 and 324 female pairs and between 41 and 169 male pairs, depending on the measure, were monozygotic (MZ) pairs discordant for depression. We use the co-twin control design in combination with prospective analyses to explore the association between a composite of predictors (perceived social support, stress, and support × stress) and depression. With familial effects included, both perceived support and stress were antecedents to, and sequelae of, depression, but no stress-buffering occurred. With familial effects controlled, stress was a sequela of a prior depressive episode, and neither lack of support nor stress were antecedents to depression, though their interaction approached significance for males. The male twin who later became depressed had previously reported lower perceived support in the face of multiple stressors compared to his co-twin who did not become depressed. We show that associations commonly observed with prospective designs are partly due to familial factors.

Dizygotic twinning rates have changed over time, which has been seen as a sign of a decline in fecundity. Since a woman's birthweight has been shown to be a marker of her fecundity, maternal birthweight may correlate with subsequent twinning rates. In the Danish National Birth Cohort (1996–2002), we examined if maternal birthweight, and whether she was born at term or preterm, correlated with her probability of multiple birth. For 20,719 live born infants, we had self-reported information about maternal birthweight, collected during the first wave of the 7-year follow-up, and information on multiple births from record linkage. The association between maternal birthweight and multiple births was investigated by use of logistic regression and presented as odds ratios (ORs) with 95% confidence intervals (CIs). Compared to women born at term with a birthweight of 3001–4000 g, women with a birthweight > 4500 g appeared to have higher chance of multiple birth while women with a birthweight of 4001–4500 had a lower chance, especially if the analysis was restricted to women with a BMI < 25 (Adjusted ORs 2.3 [1.0–5.4] and 0.4 [0.2–0.9] respectively). Odds ratios for dizygotic twinning were of the same magnitude. In women with a BMI ≥ 25, no obvious pattern was present. Our findings do not indicate that twinning is a fecundity indicator. Women with a birthweight that may indicate a pregnancy complicated with gestational diabetes had the highest rate of multiple birth. These findings are new and should be put to a critical test in other data sources.

Maternal infection with parvovirus B19 during pregnancy can cause aplastic anemia in the fetus and may lead to nonimmune fetal hydrops and fetal demise. Twin pregnancies complicated by infection due to parvovirus B19 are very rare clinical events. We present a dichorionic, diamniotic, dizygotic twin pregnancy after in vitro fertilization with parvovirus B19 infection and viral transmission to both twins, but different outcomes. At 19 weeks gestation, hydrops fetalis was diagnosed for male twin A, female twin B did not show any abnormalities. At 22 weeks gestation an acute parvovirus B19 infection was detected and twin A was diagnosed with intrauterine fetal death (IUFD) by ultrasound at 23 weeks gestation. Viral DNA was detected in maternal blood as well as in placenta and liver tissue of this twin. Twin B was born at 35 weeks gestation asymptomatically and no signs of hydrops or other congenital anomalies but viral DNA was detected by PCR in serum. At the age of 2 years, both IgG titres against B19 and parvovirus DNA amplification copies were still positive in plasma of the surviving twin, but no clinical signs were detectable. It is remarkable that both twins were infected with parvovirus B19 early in pregnancy but showed a discordant clinical outcome. Our case report describes the rare occurrence of an intrauterine fetal death (IUFD) of one twin and the asymptomatic infection of the other in a twin pregnancy.

The development of an intracranial aneurysm (IA) is a multifactorial process, involving genetic and environmental factors. The presence of IA or aneurysmal subarachnoid hemorrhage (aSAH) in twins is particularly interesting, since both genetic and environmental factors can be studied. It also raises the question of whether, when one twin is affected, the other asymptomatic twin should be examined for an IA. We report on a monozygotic (MZ) twin-pair with aSAH in both twins and we review all reported cases of IA in MZ twins. Including our case, we found only 14 MZ twin-pairs in which both twins harbored an IA, suggesting a heavy underreporting in the medical literature. In this small group, a high concordance was noted in the sites of IAs. In MZ twins, the preferred sites for IAs are the branching arteries, while aneurysms arising from fusion arteries are rare. These sites differ from the preferential sites seen in series of familial IAs and series of sporadic IAs. We therefore hypothesize that the twinning process might play a significant role in the development of IAs in MZ twins. To further explore and substantiate this, the large twin registries should be studied. Although IAs in MZ twins with a negative family history for IAs should not be regarded as familial IAs, screening of the asymptomatic twin should be seriously considered if one MZ twin presents with an aSAH or an IA, because of the high fatality rates reported in asymptomatic (and not screened) MZ twin-halves.

The purpose was to compare the sella turcica morphology of individuals within pairs of monozygotic twins with normal karyotype and to analyze the similarity between the observed morphology and the morphology of non-twins at the same age with normal karyotype. Profile radiographs from 84 individuals of 42 twin pairs (18 male and 24 female pairs, aged 18–23 years) comprised the material. Sella turcica measurements from non-twins aged 6–21 years were used as normal reference. Length, depth and diameter of the sella turcica were measured and controlled by re-measurements. Pearson's correlation coefficient was used for comparison of individuals within twin pairs. For comparison of twins and non-twins, normal standard values for length, depth and diameter were subtracted from the twin values. For the mean values of these differences, confidence limits p values and t values were calculated. The study showed that the size of the sella turcica may be partly similar and partly dissimilar within the pair of monozygotic twins. Statistical evaluation of the data showed correlations between length, depth and diameter of the sella turcica between the two twin individuals in the same twin pair. Differences in sizes are observed between individuals in the twin material and individuals in the non-twin material. As a conclusion, the twin males were more similar within the twin pair, but deviated more from the non-twin material than the females. Female twins had more discrepancy within the twin pair, but deviated less from the non-twin material than the males.

The Enrichment Study (ES) was designed to extend the Minnesota Twin Family Study (MTFS) by oversampling 11-year-old twins at especially high risk for substance use disorders by virtue of having a childhood disruptive disorder. The sample was ascertained from Minnesota birth records. To identify high-risk twins, we conducted telephone screening interviews for parent-reported symptoms of attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) as well as indications of academic disengagement. Twins who exceeded a predetermined threshold were invited to participate. To facilitate comparison with the previously ascertained MTFS participants, a random sample of 11-year-old twins was also recruited. As part of the ES study, 499 twin pairs, and their parents, visited the University of Minnesota, where each participant completed a clinical interview, psychophysiological evaluation, and thorough assessment of environmental risk. We were highly successful in recruiting at-risk twins; 52% of the screened male twins and 41% of the screened females met criteria for a diagnosis of ADHD, CD, or oppositional defiant disorder (ODD). At the pair level, 63% of the screened pairs had at least one member with a childhood disruptive disorder. This article provides an overview of the study design and includes a review of recent findings using this sample of twins.

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes.

This study presents a general model of two binary variables and applies it to twin sex pairing data from 21 twin data sources to estimate the frequency of dizygotic twins. The purpose of this study is to clarify the relationship between maximum likelihood and Weinberg's differential rule zygosity estimation methods. We explore the accuracy of these zygosity estimation measures in relation to twin ascertainment methods and the probability of a male. Twin sex pairing data from 21 twin data sources representing 15 countries was collected for use in this study. Maximum likelihood estimation of the probability of dizygotic twins is applied to describe the variation in the frequency of dizygotic twin births. The differences between maximum likelihood and Weinberg's differential rule zygosity estimation methods are presented as a function of twin data ascertainment method and the probability of a male. Maximum likelihood estimation of the probability of dizygotic twins ranges from 0.083 (95% approximate CI: 0.082, 0.085) to 0.750 (95% approximate CI: 0.749, 0.752) for voluntary ascertainment data sources and from 0.374 (95% approximate CI: 0.373, 0.375) to 0.987 (95% approximate CI: 0.959, 1.016) for active ascertainment data sources. In 17 of the 21 twin data sources differences of 0.01 or less occur between maximum likelihood and Weinberg zygosity estimation methods. The Weinberg and maximum likelihood estimates are negligibly different in most applications. Using the above general maximum likelihood estimate, the probability of a dizygotic twin is subject to substantial variation that is largely a function of twin data ascertainment method.

Current ultrasound techniques can accurately determine the chorionicity of twins, but not zygosity. We previously proposed that the zygosity of spontaneously conceived twins can be determined at early ultrasound, where 2 corpora lutea infers dizygosity, and 1 implies monozygosity. Here we did a case series, comparing zygosity predicted using this method with definitive DNA genotyping of twins after birth. We retrospectively identified 14 ultrasound reports of spontaneous twin pregnancies at 6(+0 days) to 13+6 weeks' gestation, where both ovaries were seen and the number of corpora lutea documented. We visited all twin pairs, obtained buccal smears, and determined zygosity by genotyping 9 independent microsatellite markers. All 8 cases where 2 corpora lutea were seen were dizygotic pregnancies. One further case where 3 corpora lutea were seen was also dizygotic. All 3 sets of monozygotic twins had 1 corpus luteum. There were 2 cases incorrectly assigned, where 1 corpus luteum was seen in dizygotic pregnancies. We conclude if 2 corpora lutea are seen at a first trimester ultrasound of spontaneously conceived dichorionic twins, they appear to be almost certainly dizygotic. However, if 1 corpus luteum is seen in dichorionic twins, zygosity cannot be determined with certainty since it is either monozygotic, or dizygotic where a second corpus luteum has been missed.

A review of twin research on cleft lip and palate is presented. This information is accompanied by a look at the lives of young monozygotic (MZ) male triplets concordant for cleft lip, but discordant for the type and placement of the cleft and for the presence of cleft palate. Research on depression in mothers and fathers of twins conceived naturally and by artificial reproductive techniques follows. Current findings and implications of epigenetic differences in MZ twins are also summarized. Interesting life history events surrounding MZ twin chefs and table tennis players, as well as plans to construct the world's largest twin registry, are presented in the final section.

Studies have reported that refractive errors are associated with premature births. As twins have higher prevalence of prematurity than singletons, it is important to assess similarity of the prevalence of refractive errors in twins and singletons for proper interpretations and generalizations of the findings from twin studies. We compared refractive errors and diopter hours between 561 pairs of twins and 3757 singletons who are representative of school-age children (7–15 years) residing in an urban area of southern China. We found that the means and variances of the continuous measurement of spherical equivalent refractive error and diopter hours were not significantly different between twins and singletons. Although the prevalence of myopia was comparable between twins and singletons, that of hyperopia and astigmatism was slightly but significantly higher in twins than in singletons. These results are inconsistent with those of adult studies that showed no differences in refractive errors between twins and singletons. Given that the sample size of twins is relatively small and that this study is the first to demonstrate minor differences in refractive errors between twins and singletons, future replications are necessary to determine whether the slightly higher prevalence of refractive errors in twins than in singletons found in this study was due to a sampling error or to the developmental delay often observed in twins in childhood.

Theorems, proofs, laws and rules are commonly named according to the presumed investigator, but often earlier investigators have contributed substantially to the findings. One example of this is Hellin's law, which was named after Hellin, although he was not the first to discover it. In research on twinning and higher multiple maternities, the law has played a central role because it is approximately correct, despite showing discrepancies that are difficult to explain or eliminate. Several improvements to this law have been proposed. In this study, we re-examine some old papers to provide an overview of the scientists who have contributed to the genesis and the improvements of this law. In addition, we consider more recent contributions in which Hellin's law has been discussed and evaluated. It has been mathematically proven that Hellin's law does not hold as a general rule. However, most studies are based on empirical rates of multiple maternities, ignoring random errors. Such studies can never confirm the law, but only serve to identify errors too large to be characterized as random.

Objective: Discordance in nuchal translucency measurements in monochorionic diamniotic twin pregnancies was assessed as predictor of Twin-to-Twin Transfusion Syndrome. Study Design: A total of 61 monochorionic diamniotic twins were enrolled. Nuchal translucency (NT) and crown-rump-length (CRL) discordance was calculated as the percentage of delta NT and CRL (absolute difference NT/CRL fetus 1 and fetus 2) of the largest measurement, and correlated with subsequent development of Twin-to-Twin Transfusion Syndrome. Results: Twin-to-Twin Transfusion Syndrome developed in 14/61 (23%) of cases. A NT discordance of 20% or more best predicted Twin-to-Twin Transfusion Syndrome development, with a sensitivity of 64% and a specificity of 78%. We found a positive predictive value of 50% and negative predicted value of 86% for Twin-to-Twin Transfusion Syndrome development if NT discordance was 20% or more. Conclusion: NT discordance of more than 20% in monochorionic diamniotic twins is associated with an increased risk for subsequent development of Twin-to-Twin Transfusion Syndrome, and with earlier presentation of symptoms.

The goals, prospects and methods of the Prospective Twin Registry in Southwestern China (TRiSC) are described. The aim of this study is to measure children's behavioral development and psychopathology from phenotypic, genetic and environmental perspectives. It focuses on measuring children's behavior and psychopathology from child self-reports, as well as parental and teacher informant reports, and relating it to the children's general cognitive abilities, and to the parenting style in the family. Other variables of interest such as children's temperament and parental health status are discussed, as well as plans for further research.

Ahigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n = 138) and within twin pair (n = 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (β) = 0.023 (95% confidence interval, –0.062–0.108), p = 0.592 and β = 0.038 (–0.080–0.156), p = 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.