Placentation in multiple births.

Outcomes of multifetal pregnancy in prenatal life are markedly affected by chorionicity. Several disease processes are found in monochorionic (MC) twins that do not occur in dichorionic (DC) twins. Improvements in prenatal outcomes will depend on reliable first trimester diagnosis of chorionicity, allowing early monitoring for complications of MC placentation. Particular structures and functions of MC twin placentas affect outcomes and can be targeted for specific treatments, especially in twin-twin transfusion. The causes of severe DC twin fetal growth discordance are clarified. In post-natal life, zygosity is a determining effect in genetic predisposition to many chronic diseases, including neoplasia. Few MC twins know that they are monozygotic (MZ). Few twin researchers realize that MZ twins may be genetically discordant. Abandonment of the word "identical" for MZ twins would assist in clarifying these issues of zygosity, concordance and discordance.     

Excess of twins among affected sibling pairs with autism: implications for the etiology of autism

It is widely accepted that genes play a role in the etiology of autism. Evidence for this derives, in part, from twin data. However, despite converging evidence from gene-mapping studies, aspects of the genetic contribution remain obscure. In a sample of families selected because each had exactly two affected sibs, we observed a remarkably high proportion of affected twin pairs, both MZ and DZ. Of 166 affected sib pairs, 30 (12 MZ, 17 DZ, and 1 of unknown zygosity) were twin pairs. Deviation from expected values was statistically significant (P<10(-6) for all twins); in a similarly ascertained sample of individuals with type I diabetes, there was no deviation from expected values. We demonstrate that to ascribe the excess of twins with autism solely to ascertainment bias would require very large ascertainment factors; for example, affected twin pairs would need to be, on average, approximately 10 times more likely to be ascertained than affected non-twin sib pairs (or 7 times more likely if "stoppage" plays a role). Either risk factors (related to twinning or to fetal development) or other factors (genetic or nongenetic) in the parents may contribute to autism.     

Zygosity diagnosis in the absence of genotypic data: an approach using latent class analysis.

For zygosity diagnosis in the absence of genotypic data, or in the recruitment phase of a twin study where only single twins from same-sex pairs are being screened, or to provide a test for sample duplication leading to the false identification of a dizygotic pair as monozygotic, the appropriate analysis of respondents' answers to questions about zygosity is critical. Using data from a young adult Australian twin cohort (N = 2094 complete pairs and 519 singleton twins from same-sex pairs with complete responses to all zygosity items), we show that application of latent class analysis (LCA), fitting a 2-class model, yields results that show good concordance with traditional methods of zygosity diagnosis, but with certain important advantages. These include the ability, in many cases, to assign zygosity with specified probability on the basis of responses of a single informant (advantageous when one zygosity type is being oversampled); and the ability to quantify the probability of misassignment of zygosity, allowing prioritization of cases for genotyping as well as identification of cases of probable laboratory error. Out of 242 twins (from 121 like-sex pairs) where genotypic data were available for zygosity confirmation, only a single case was identified of incorrect zygosity assignment by the latent class algorithm. Zygosity assignment for that single case was identified by the LCA as uncertain (probability of being a monozygotic twin only 76%), and the co-twin's responses clearly identified the pair as dizygotic (probability of being dizygotic 100%). In the absence of genotypic data, or as a safeguard against sample duplication, application of LCA for zygosity assignment or confirmation is strongly recommended.     

The Danish Twin Registry: 127 birth cohorts of twins.

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.     

Genetic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies

Background

Acute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect.

Methods

We searched PubMed/MEDLINE, ISI Web of Science, EMBASE, and Google Scholar from their inception to 31 January 2011, and bibliographies of retrieved articles, for twin studies of the concordance for acute rheumatic fever or rheumatic heart disease in monozygotic versus dizygotic twins that used accepted diagnostic criteria for acute rheumatic fever and zygosity without age, gender or language restrictions. Twin similarity was measured by probandwise concordance rate and odds ratio (OR), and aggregate probandwise concordance risk was calculated by combining raw data from each study. ORs from separate studies were combined by random-effects meta-analysis to evaluate association between zygosity status and concordance. Heritability was estimated by fitting a variance components model to the data.

Results

435 twin pairs from six independent studies met the inclusion criteria. The pooled probandwise concordance risk for acute rheumatic fever was 44% in monozygotic twins and 12% in dizygotic twins, and the association between zygosity and concordance was strong (OR 6.39; 95% confidence interval, 3.39 to 12.06; P<0.001), with no significant study heterogeneity (P = 0.768). The estimated heritability across all the studies was 60%.

Conclusions

Acute rheumatic fever is an autoimmune disorder with a high heritability. The discovery of all genetic susceptibility loci through whole genome scanning may provide a clinically useful genetic risk prediction tool for acute rheumatic fever and its sequel, rheumatic heart disease.     

Craniofacial anomalies in twins

Studies of twins provide insight into the relative contribution of genetic and environmental factors in the causality of structural anomalies. Thirty-five affected twin pairs were identified from a group of 1114 patients with congenital craniofacial deformities evaluated from 1972 to 1989. Forty-three of these 70 twins exhibited one or more craniofacial anomalies; these were analyzed for dysmorphic characteristics, zygosity, concordance, and family history. The anomalies were categorized into two groups: malformations and deformations. The malformations (n = 36) included hemifacial microsomia (n = 10), cleft lip and palate (n = 8), cleft palate (n = 4), rare facial cleft (n = 2), craniosynostosis (n = 2), Binder syndrome (n = 2), Treacher Collins syndrome (n = 2), craniopagus (n = 2), CHARGE association (n = 1), frontonasal dysplasia (n = 2), and constricted ears (n = 1). The deformations (n = 7) included plagiocephaly (n = 5), hemifacial hypoplasia (n = 1), and micrognathia (n = 1). Twenty-one monozygotic and 14 dizygotic twin pairs were identified. The concordance rate was 33 percent for monozygotic twins and 7 percent for dizygotic twins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Familial factors in early deaths: Twins followed 30 years to ages 51–61 in 1978

Summary Subjects in the National Academy of Sciences-National Research Council Twin Registry of 31,848 male twin veterans were followed for mortality from 1 January 1946, or from the date of entry into military service if that was later, to 31 December 1978. During this time 3,573 deaths occurred among them, 837 due to trauma and 2,712 due to disease.Mortality from all causes for the entire follow-up period was 10.2% among 11,350 monozygotic (MZ) twins and 11.4% among 14,450 dizygotic (DZ) twins. Mortality of veterans is known to be favorable compared to U.S. males. Among U.S. males of the same ages as the two respective twin zygosity groups, a mortality of 13.9% would have been expected during this time period. Observed mortality from trauma was 2.3% for MZ twins and 2.5% for DZ twins, with 3.0% expected in either group. Observed mortality from all disease was 7.9% for MZ twins and 8.8% for DZ twins, with 10.9% expected in either group.For total mortality, the case twin concordance rates, based on individual deaths, were 28.2% among MZ twins and 17.7% among DZ twins. For trauma, respectively by zygosity, these concordance rates were 6.9% and 3.9%. In this sample, familial factors appear to be of little consequence in trauma deaths. For all disease the concordance rates were 30.1% and 17.4%. Estimating heritability of liability to death from disease, as proposed by Edwards (1969), provides values of h ²=r=0.51 for MZ twins, h ²=2r=0.48 for DZ twins, and h ₂=2(r _MZ–r _DZ=0.54 using data for the two zygosity groups combined.Presented in abbreviated form at The Third International Congress of Twin Studies, Jerusalem, Israel, 19 June 1980     

Comparing sensory experience in bitter taste perception of phenylthiocarbamide within and between human twins and singletons: intrapair differences in thresholds and genetic variance estimates

BACKGROUND: Quantitative genetic studies revealed that not all of the phenotypic variance in PTC taste perception is heritable. AIM: To study quantitative variations in PTC tasting ability in twins and to estimate heritability of PTC taste perception on the taste of twin data on males and females sexes separately. SUBJECTS AND METHODS: The data for PTC taste sensitivity following the classic method of Harris & Kalmus (1949) were collected on a sample of 141 twin pairs (66 MZ and 75 DZ) and 275 singletons (128 males and 147 females) from Chandigarh, India. Genetic analyses were performed following Christian (1979), Donner (1986) and Sham (1998). RESULTS: Frequency of non-tasters was similar in twins (33 %) and singletons (32 %), but significant sex differences were observed. No differences were found between zygosities for mean thresholds. Similarly, no evidence of variance heterogeneity and environmental covariance was seen between zygosities. Since no basic assumption of the twin method was found violated, within-pair estimates of genetic variance would be unbiased. These estimates were highly significant in both males and females. However, dominance and additive components of genetic variance were found to differ between sexes. CONCLUSION: PTC thresholds do not seem to be significantly affected by environmental factors as no variance inequality was observed between twin zygosities. Intensity of bitterness (scalar dimensions) of PTC is a separate trait having no commonality with the genetic basis of recognition threshold for PTC tasting ability. The receptors recognizing bitter taste are different from the receptors determining intensity of taste. The absolute difference between co-twins in PTC thresholds can be used as a simple tool in the twin zygosity diagnosis. The results show that none of the MZ co-twins had manifested difference of more than 3 in their PTC threshold.     

The influence of zygosity and chorion type on fat distribution in young adult twins consequences for twin studies.

An adverse intra-uterine environment has been associated with abdominal fat distribution in singletons. Twins often have a low birth weight and a short gestation. Therefore, they may have an increased risk to develop abdominal obesity. Furthermore, monozygotic monochorionic twins (MZ MC) have a larger intra-pair birth weight difference compared to monozygotic dichorionic twins (MZ DC). If adult anthropometry is programmed in utero, this may affect the intra-pair correlations in adulthood and, consequently, also the results from the classic twin method to estimate genetic and environmental influences. In the present study, we compared the absolute values, the intra-pair differences, and the intra-pair correlations of body mass, height, BMI, and abdominal fat distribution of 424 MZ MC, MZ DC and dizygotic (DZ) twin pairs (aged 18-34 yrs). DZ, MZ DC and MZ MC twins did not differ for most anthropometric characteristics. Only MZ women tended (p = 0.03) to accumulate more abdominal fat compared to DZ twins. Overall, the contribution of zygosity and chorion type to adult anthropometry was rather low (< or = 1.7%). Although the intra-pair birth weight difference of MZ MC pairs (10.5% in men, 12.3% in women) was significantly larger compared to that of MZ DC pairs (6.9% and 9.2% resp.), the intra-pair differences in adult anthropometry were similar for both MZ twin types. Also the intra-pair correlations of MZ MC and MZ DC pairs were strikingly alike, suggesting no significant influence of the prenatal environment on adult concordance. In conclusion, the substantial difference in the prenatal environment of MZ MC and MZ DC twins did not result in a difference in intra-pair concordance of adult anthropometry and fat distribution. Therefore, we suggest that the chorion type of MZ twins does not bias the twin design and the estimation of the genetic contribution to adult anthropometry.     

Diagnosing zygosity in infant twins: physical similarity, genotyping, and chorionicity.

We compared the results of different methods for diagnosing zygosity in a sample of 237 same-sex pairs of twins assessed at 5 and 18 months of age. Despite the twins' very young age and early stage of development, physical similarity was concordant with genotyping in 91.9% of cases at 5 months and 93.8% of cases at 18 months, for a subsample of 123 and 113 pairs, respectively. This concordance rate was obtained following a case-by-case assessment of each pair's physical similarity using a shortened version of the Zygosity Questionnaire for Young Twins (Goldsmith, 1991). Taking into account the chorionicity data available from the twins' medical files, we were able to classify correctly 96% of the pairs, an accuracy rate comparable to previously reported rates obtained with older twins. Chorionicity data is especially useful since we found that monochorionic MZ twins are more difficult than dichorionic MZ twins to diagnose by physical similarity at these young ages. The relative cost-benefit of methods based on reported physical similarity and DNA analysis is discussed in light of these results.     

Sex and genetic differences in hair color changes during early childhood.

Hair color was assessed routinely from three months to six years for children participating in a longitudinal study of twins: 169 female twin pairs, 161 male pairs, and 60 opposite-sex pairs. Age trends, established by sampling only one number of every pair, showed marked changes in hair color for both sexes, but there was a consistent excess of light-haired males and dark-haired females. Within-pair concordance rates were calculated for same-sex pairs whose zygosity had been determined independently through bloodtyping. A high rate of concordance was found for MZ twins at every age in spite of the general change in hair color, indicating a strong genetic influence in the timing of color changes. The results are discussed in terms of accelerated maturation of females, and the need for genetic models of the inheritance of hair color which are age- and sex-specific.     

Norwegian Twin Registers and Norwegian twin studies--an overview.

The Norwegian Twin Registers include several sets of population-based sub-registers, and covers twin pairs born between 1895 and today. Except for the missing birth years 1960 to 1967, the register is almost complete. Most of the register contains information about both same-sexed and opposite-sexed twin pairs, except for twin pairs born between 1946 and 1960, where only same-sexed twins are registered. In a substantial part of the register, information about zygosity is obtained, mainly by a mailed questionnaire and in some cases supported by DNA testing. These are the birth years 1915 to 1960 and the birth years 1967 to 1979. Zygosity information is further obtained in the different twin studies derived from the twin register. In 1990 the whole register was made available in a computerized form. Several twin studies have been derived from the different parts of the register. In this article, studies from the two earliest parts of the register are reviewed and grouped by recruitment specifics. Finally, future plans for the register and twin studies are discussed.     

Glucocorticoid receptor binding in twin pairs is affected by shared environment but not by shared genes

We set out to determine whether glucocorticoid receptor activity is affected mainly by genetic or environmental factors. The affinity and capacity of the glucocorticoid receptor was measured using dexamethasone binding in whole leukocytes from 53 monozygotic and 48 dizygotic twin pairs. Receptor binding characteristics assayed from twin pairs on the same day were highly correlated within twin pairs irrespective of zygosity. Apparent Kd was negatively correlated with environmental temperature (R²=0.13, P<0.0001) but this did not confound the intra-pair correlation, suggesting a strong familial component independent of zygosity. Receptor binding parameters were not more closely correlated in monozygotic twins than dizygotic twin pairs indicating that there is no major genetic contribution to receptor binding and that environmental influences predominate. The close similarity in binding between twin pairs in adulthood raises the possibility that familial, non-genetic, factors such as shared early life environment may programme the glucocorticoid receptor.     

Inter-twin relationships and mental health.

We evaluated dominance-submissiveness between co-twins and its relationship to mental health in a cohort study of 419 twins followed from pregnancy to 22-30 years of age. Dominance-submissiveness between co-twins was assessed from three separate perspectives: physical dominance, psychological dominance, and verbal dominance. Depressive, nervous, and psychosomatic symptoms were analyzed in different twin groups. In the physical domain, males were more commonly dominant than females at school age and in adulthood. Before and at school age, girls were more dominant than boys in the psychological and verbal domains, as well as in total dominance. These differences disappeared in adulthood, and 81% of adult twins felt themselves equal to their co-twin in total dominance. Submissiveness in the psychological domain seemed to be associated with increased depressiveness, nervous complaints and psychosomatic symptoms in males of male-female twin pairs. Verbally submissive males in same-sex twin pairs had more depression and psychosomatic symptoms. Among females of same-sex twin pairs, submissiveness in the psychological domain was most clearly associated with depressive symptoms, whereas psychological or verbal dominance-submissiveness among females from male-female twin pairs was not associated with symptoms. Psychologically dominant males and females of same-sex twin pairs expressed greater nervousness than did their co-twins. We conclude that being submissive, especially in the psychological domain, to a female twin partner seems to be stressful, whereas it is easier, especially for females, to be submissive to a male twin partner.     

Viruses and the aetiology of diabetes: a study in identical twins.

Sera were collected from 49 pairs of identical twins, 27 of whom were discordant (only one twin affected) and 22 concordant (both diabetic) for insulin-dependent diabetes. All were tested for antibodies to mumps, cytomegalovirus, rubella, Coxsackie virus types B1-5, and Mycoplasma pneumoniae. The diabetic co-twins had no more antibodies to any of the viruses than the non-diabetic co-twins of the discordant pairs. Antibodies to Coxsackie B2, rubella virus, and M pneumoniae were found more often in the discordant than in the concordant twins. In 30 of the 71 diabetic twins symptoms began when they were aged 4-6 years or 10-15 years. More concordant than discordant twins were diagnosed during the months January to March. Hence there was no direct evidence of a virus aetiology of juvenile onset diabetes in these twins, and the difference in antibody titres between the concordant and discordant twins was in keeping with a genetic difference between them. The age and time of onset suggested that environmental factors may be important in causing diabetes in the twins.     

Differences and similarities in the intra-uterine behaviour of monozygotic and dizygotic twins.

Diagnostic advances have made it possible to use ultrasonograph to assess placentation and therefore zygosity in utero in the case of monochorionic-monozygotic twins. Foetal behaviour of 15 monozygotic and 15 unlike-sexed dizygotic twin pairs was studied serially with ultrasounds from 10 to 22 weeks gestational age. Each twin, regardless of its zygosity, showed individualised behavioural styles. One twin was found to be 'dominant' in the sense of being more active, but less reactive, possibly due to the fewer stimuli being generated by its co-twin. Monozygotic twins, as opposed to dizygotic twins, showed greater similarities in activity and reactivity levels, but were never behaviourally identical and decreased in likeness with increasing age. Our data suggest that so-called identical twins are very similar, but not behaviourally identical, from very early in pregnancy. The unequally shared intrauterine environment contributes to putting each monozygotic twin on a progressively distinct behavioural path.     

Zygosity diagnosis in young twins by parental report.

This study reports on zygosity determination in twins of childhood age. Parents responded to questionnaire items dealing with twin similarity in physical characteristics and frequency of mistaking one twin for another by parents, relatives and strangers. The accuracy of zygosity diagnosis was evaluated across twins aged 6, 8, and 10 and across parents. In addition, it was examined whether the use of multiple raters and the use of longitudinal data lead to an improvement of zygosity assignment. Complete data on zygosity questions and on genetic markers or blood profiles were available for 618 twin pairs at the age of 6 years. The method used was predictive discriminant analyses. Agreement between zygosity assigned by the replies to the questions and zygosity determined by DNA markers/blood typing was around 93%. The accuracy of assignment remained constant across age and parents. Analyses of data provided by both parents and collected over multiple ages did not result in better prediction of zygosity. Details on the discriminant function are provided.     

Determination of twin zygosity: a comparison of DNA with various questionnaire indices.

This study examined cross-validation and test-retest reliability of questions and questionnaire indices commonly used for twin zygosity classification. Mothers of 58 monozygotic (MZ) and 52 dizygotic (DZ) same sex twin pairs were interviewed by telephone to answer questions regarding the similarity of their twins (mean age = 14.6 +/- 2.8 years). A logistic regression equation correctly classified 91% of both MZ and DZ twin pairs in our sample using 7 of the 12 zygosity questions. The internal consistency for the total questionnaire (Cronbach's alpha) was 0.88. The median two month temporal stability estimate for the individual questions was r = .56 and r = .79 for the test total. For the cross-validation, zygosity classification indices taken from 9 previous studies were applied to our sample and compared to classification according to DNA microsatellite analyses (agreement range = 44 to 100%). The accuracy of the classification indices was significantly lower than the original studies for 62% of the comparisons. If zygosity determination with DNA markers or blood group typing for all subjects is not feasible, rather than using classification indices based on other studies, an optimal classification scheme can be achieved by using a zygosity questionnaire of which the reliability and validity of the questions is established in a random subsample of the same twin cohort.     

Determination of Zygosity in Adult Chinese Twins Using the 450K Methylation Array versus Questionnaire Data

Previous studies have shown that both single nucleotide polymorphisms (SNPs) and questionnaires-based method can be used for twin zygosity determination, but few validation studies have been conducted using Chinese populations. In the current study, we recruited 192 same sex Chinese adult twin pairs to evaluate the validity of using genetic markers-based method and questionnaire-based method in zygosity determination. We considered the relatedness analysis based on more than 0.6 million SNPs genotyping as the golden standards for zygosity determination. After quality control, qualified twins were left for relatedness analysis based on identical by descent calculation. Then those same sex twin pairs were included in the zygosity questionnaire validation analysis. Logistic regression model was applied to assess the discriminant ability of age, sex and the three questions in zygosity determination. Leave one out cross-validation was used as a measurement of internal validation. The results of zygosity determination based on 65 SNPs in 450k methylation array were all consistent with genotyping. Age, gender, questions of appearance confused by strangers and previously perceived zygosity consisted of the most predictable model with a consistency rate of 0.8698, cross validation predictive error of 0.1347. For twin studies with genotyping and\or 450k methylation array, there would be no need to conduct other zygosity testing for the sake of costs consideration.     

The foetal origins of adult disease: interpreting the evidence from twin studies.

Twin studies have a contribution to make to the debate concerning the foetal origins of adult disease. Twins are growth retarded compared to singletons and experience post-natal catch-up growth. However, there is no evidence that twins are at increased risk of cardiovascular disease. Studying whether discordance in size at birth within monozygotic twin pairs is predictive of discordance in later life disease should help resolve whether the association between size at birth and later disease is due to common genetic factors. Results from studies of blood pressure in childhood and adult life looking at these within twin effects are far from conclusive. There are, however, methodological problems in the interpretation of these results, not least of which is the relatively small numbers of twin pairs studied. Studies exploring the effect of zygosity and chorion type on later disease provide may provide a useful extension of the research agenda. In summary, twin studies to date have raised more questions about the foetal origins hypothesis than they have resolved.