Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus.

OBJECTIVE: To study the comparative importance of environment and genes in the development of islet cell autoimmunity associated with insulin dependent diabetes mellitus. DESIGN: Population based study of diabetic twins. SETTING: Danish population. SUBJECTS: 18 monozygotic and 36 dizygotic twin pairs with one or both partners having insulin dependent diabetes. MAIN OUTCOME MEASURES: Presence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase (GAD65) in serum samples from twin pairs 10 years (range 0-30 years) and 9.5 years (2-30 years) after onset of disease. RESULTS: In those with diabetes the prevalence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase in the 26 monozygotic twins was 38%, 85%, and 92%, respectively, and in the dizygotic twins was 57%, 70%, and 57%, respectively. In those without diabetes the proportions were 20%, 50%, and 40% in the 10 monozygotic twins and 26%, 49%, and 40% in the 35 dizygotic twins. CONCLUSION: There is no difference between the prevalence of islet cell autoantibodies in dizygotic and monozygotic twins without diabetes, suggesting that islet cell autoimmunity is environmentally rather than genetically determined. Furthermore, the prevalence of islet cell antibodies was higher in the non-diabetic twins than in other first degree relatives of patients with insulin dependent diabetes. This implies that the prenatal or early postnatal period during which twins are exposed to the same environment, in contrast with that experienced by first degree relatives, is of aetiological importance.     

Size at birth, fasting glucose and insulin levels and insulin resistance in adult twins.

Studies in singletons have found an association between birthweight and Type 2 diabetes in adult life. The aim of this study was to investigate whether this association could also be seen in twins. 59 monozygotic (MZ) and 69 dizygotic (DZ) same-sex twin pairs aged 19-50 years and 89 singleton controls matched for age, gestational age, gender, maternal age and parity were recruited from a local obstetric database. Associations between adult glucose, HbA(1)C and insulin levels and insulin resistance and birthweight were assessed by linear regression with adjustment for confounding variables. Twins were significantly lighter at birth than singleton controls, but there were no significant differences in adult weight, glucose, HbA(1)C and insulin levels or insulin resistance between twins and controls. The relationship between birthweight and fasting glucose and insulin levels, and insulin resistance was not significantly different from zero in either twins or controls, but birthweight was significantly negatively associated with HbA(1)C only in controls. There was no evidence of a difference between MZ and DZ twins in unpaired or within-pair analysis. These results provide little evidence that low birthweight in twins increases the risk of impaired glucose-insulin metabolism in young adults or that genetic factors can account for the association observed in singletons.     

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.     

Heritability of eleven metabolic phenotypes in Danish and Chinese twins: A cross‐population comparison

Objectives : A twin‐based comparative study on the genetic influences in metabolic endophenotypes in two populations of substantial ethnic, environmental, and cultural differences was performed. Design and Methods : Data on 11 metabolic phenotypes including anthropometric measures, blood glucose, and lipids levels as well as blood pressure were available from 756 pairs of Danish twins (309 monozygotic and 447 dizygotic twin pairs) with a mean age of 38 years (range: 18‐67) and from 325 pairs of Chinese twins (183 monozygotic and 142 dizygotic twin pairs) with a mean age of 40.5 years (range: 18‐69). Twin modeling was performed on full and nested models with the best fitting models selected. Results : Heritability estimates were compared between Danish and Chinese samples to identify differential genetic influences on each of the phenotypes. Except for hip circumference, all other body measures exhibited similar heritability patterns in the two samples with body weight showing only a slight difference. Higher genetic influences were estimated for fasting blood glucose level in Chinese twins, whereas the Danish twins showed more genetic regulation over most lipids phenotypes. Systolic blood pressure was more genetically controlled in Danish than in Chinese twins. Conclusions : Metabolic endophenotypes show disparity in their genetic determinants in populations under distinct environmental conditions.     

Mortality among twins after age 6: fetal origins hypothesis versus twin method.

OBJECTIVE--To test the validity of the fetal origins hypothesis and the classic twin method. DESIGN--Follow up study of pairs of same sex twins in which both twins survived to age 6. SETTING--Denmark. SUBJECTS--8495 twin individuals born 1870-1900, followed through to 31 December 1991. MAIN OUTCOME MEASURES--Mortality calculated on a cohort basis. RESULTS--Mortality among twins and the general population was not significantly different except among females aged 60-89, in whom mortality among twins was 1.14 times (SE 0.03) higher than in the general population. Mortality among female dizygotic twins was 1.77 times (0.18) higher than among monozygotic twins at age 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age 6. CONCLUSION--According to the fetal origins hypothesis the risk of adult morbidity and mortality is heightened by retardation in intrauterine growth. Twins, and in particular monozygotic twins, experience growth retardation in utero. The findings in the present study suggest that the fetal origins hypothesis is not true for the retardation in intrauterine growth experienced by twins. Furthermore, the data are inconsistent with the underlying assumption of a recent claim that the classic twin method is invalid for studies of adult diseases. The present study is, however, based on the one third of all pairs of twins in which both twins survived to age 6. The possible impact of this selection can be evaluated in future studies of cohorts of younger twins with lower perinatal and infant mortality.     

Plantar pressures in identical and non-identical twins

Identifying environmental risk factors for musculoskeletal disorders is challenging due to the number of potential confounders. Twins are of particular interest for researchers interested in studying these types of problems due to their inherent control for the influence of genetic factors. In twin studies, this population can allow environmental risk factors to be more easily identified, and this type of study design may allow the role of biomechanics in injury and disease to be further explored. At present, it is unclear if foot function displays more similarity between certain types of twins. In this study, we hypothesized that the plantar pressures of monozygotic (identical) twins would be more similar between pairs than dizygotic (non-identical) twins. We measured static and dynamic plantar pressures from five pairs of each twin type. Statistical parametric modeling was used to compare pressure distributions at the sensor level. For >80% of stance phase, the pixel level analysis indicated that monozygotic twins had less variation in plantar pressure between pairs. The average z-statistic across the entire trial was 0.88 for the monozygotic group and 1.13 for the dizygotic group. In this study we provide evidence of greater similarity of plantar pressures in monozygotic twin pairs compared to dizygotic twins. This finding supports the use of co-twin studies investigating potentially modifiable environmental and biomechanical risk factors for musculoskeletal conditions that affect the foot and ankle.     

The potential use of artificially produced monozygotic twins for comparative experiments

The uniformity of twins has been examined by assembling estimates of the intraclass correlation coefficient (rho(I)) available in the literature for a variety of parameters studied in cattle monozygotic twins and human dizygotic and monozygotic twins. The values of rho(I) vary considerably between parameters. In human monozygotic twins rho(I) is always larger compared to that found in dizygotic twins. There is insufficient evidence to determine whether artificial monozygotic twins are more uniform than natural monozygotic twins. A new measure of twin uniformity, given by T (3) = 1 (1-rho (I)) , is introduced. In practice 2T(3) gives the number of animals chosen at random that one member of a twin pair can replace without loss of statistical efficiency. A useful class of experimental designs for the exploitation of twin uniformity is incomplete block designs. These designs are defined by (v, k, b), where v is the number of treatments to be compared, k = 2, and b is the number of twin pairs. Each design has an associated efficiency (E). Provided rho(I)>1-E, an incomplete block design will be advantageous. In general, when only a few twin pairs are available, this relation will only hold for monozygotic and not dizygotic twins. Suitable arrangements of treatment comparisons for designs (3,2,8), (4,2,9), (5,2,10), (6,2,11) are presented.     

The role of the placenta in variability of fetal exposure to cocaine and cannabinoids: a twin study.

There is wide variability in the reported adverse fetal effects of cocaine and cannabinoids. The causes of this variability are largely unknown. We hypothesized that variability in placental handling of drugs affect fetal exposure. We used twin pregnancies as a paradigm to address the role of the placenta in this variability. We analyzed hair or meconium samples taken from dizygotic and monozygotic twins exposed in utero to illicit drugs. Out of 12 pairs, 5 had negative levels in both twins, and seven pairs of twins had chemical evidence of fetal exposure to cocaine (n = 5) or cannabinoids (n = 2). The one known monozygotic pair of twins had almost identical levels of cocaine. In contrast, the six dizygotic pairs had large disparities in either cocaine or cannabinoid concentrations. In three of these six dizygotic pairs, levels of cocaine (n = 2) or canabinoids (n = 1) were undetectable in one twin while positive in the other. Given that twins are theoretically exposed to similar maternal drug levels, our findings suggest that the placenta may have a major role in modulating the amounts of drug reaching the fetus.     

Twin births to mothers who are twins: a registry based study.

OBJECTIVES: To estimate the risk of having twin infants for mothers who are twins; to investigate the genetic influence on twinning. DESIGN: Retrospective study of multiple births in two nationwide registries. SETTING: Sweden. SUBJECTS: Multiple births among 31,586 deliveries between 1973 and 1991 to women who were twins. MAIN OUTCOME MEASURES: Numbers of monozygotic and dizygotic twin births expected and estimated. RESULTS: Women who are dizygotic twins have a moderately increased risk of having twins (relative risk 1.30, 95% confidence interval 1.14 to 1.49) which seems to be completely the result of dizygotic twinning. When a mother is a monozygotic twin, her risk of having twins of the same sex is significantly increased (1.47; 1.10 to 1.97). This is the result of an excess of monozygotic twins (39 pairs estimated, 18 expected). CONCLUSIONS: Women who are twins have an increased risk of giving birth to twins. Genetic components of monozygotic and dizygotic twinning seem to be independent.     

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.     

X inactivation as a source of behavioural differences in monozygotic female twins.

Although members of monozygotic twin pairs are identical in genome sequence, they may differ in patterns of gene expression. One early and irreversible process affecting gene expression, which can create differences within pairs of female monozygotic twins, is X inactivation - one twin can express mainly paternally-received genes on the X chromosome while the other twin expresses mainly maternally-received genes. It follows that non-identical X chromosome expression may cause female monozygotic twins to correlate less strongly than male monozygotic twins on complex behavioural traits affected by X-linked loci. We tested this hypothesis using data from around 4000 same-sex twin pairs on 9 social, behavioural and cognitive measures at ages 2, 3 and 4. Consistent with our hypothesis, monozygotic males were generally more similar than monozygotic females. Three of four significant differences were in traits showing higher correlations in males than females, and these traits - prosocial behaviour, peer problems, and verbal ability - have all been proposed previously in the literature as being influenced by genes on the X chromosome. Interestingly, dizygotic twins showed the reverse pattern of correlations for similar variables, which is also consistent with the X inactivation hypothesis; taken together, then, our monozygotic and dizygotic results suggest the presence of quantitative trait loci on the X chromosome.     

The influence of genetic and environmental factors on the etiology of the human umbilical cord: the East Flanders prospective twin survey

The umbilical cord is vulnerable to a number of insults that may alter cord morphology, diminish cord flow, and ultimately compromise fetal nutrition. Thus, an investigation of the underlying mechanisms of the development of cord morphology and possible pathologies associated with it may provide insight regarding fetal growth in the intrauterine environment and have an impact on later development of the child. To our knowledge, this study, which included 11,980 twins, is the first to report the relative contribution of genes and environment in the development of the cord. Umbilical cord length, insertion, knots, twisting, and number of vessels were examined by trained midwives at birth. Means and percentages of cord characteristics by twin zygosity/chorionicity and gender were calculated. ANOVA and chi-square tests were performed to calculate discordance in cord morphology between dizygotic (DZ), monozygotic monochorionic (MZMC), and monozygotic dichorionic (MZDC) twins. Univariate genetic models were fit to the umbilical cord characteristics to investigate the genetic and environmental influences on umbilical cord morphology. Mainly nonshared environmental but also genetic factors influence umbilical cord morphology. In MZMC male and female twins, a peripheral/marginal cord insertion was significantly (P < 0.01) more prevalent compared to MZDC and DZ male and female twins, respectively. In MZMC male twins, clockwise twisting was significantly (P = 0.02) less frequent compared to DZ twins. Environmental and genetic factors influence cord morphology and pathology. Twin members can experience environmental influences that are not shared between them even in that very early stage of in utero life.     

Genetic influences on dentition and dental arch dimensions: a study of monozygotic and dizygotic triplets

Previous studies of the tooth and dental arch dimensions in twins have suggested that the size and form of the dentition is more under genetic control than the size and form of the dental arch. A study of dentition and dental arch was carried out on three sets of same-sex triplets, two sets being monozygotic and one set dizygotic. No significant differences were found in the dental arch dimensions in any set of the triplets. The tooth dimensions showed no significant differenes in the monozygotic triplet sets or in the monozygotic pair from the dizygotic triplet set, but showed significant differences between the monozygotic pair and the third member of the dizygotic set. This confirms the data obtained from twin studies.     

Evidence for higher heritability of somatotype compared to body mass index in female twins

The influence of genetics on human physique and obesity has been addressed by the literature. Evidence for heritability of anthropometric characteristics has been previously described, mainly for the body mass index (BMI). However, few studies have investigated the influence of genetics on the Heath-Carter somatotype. The aim of the present study was to assess the heritability of BMI and somatotype (endomorphy, mesomorphy, and ectomorphy) in a group of female monozygotic and dizygotic twins from childhood to early adulthood. A total of 28 females aged from 7 to 19 years old were studied. The group included 5 monozygotic and 9 dizygotic pairs of twins. The heritability was assessed by the twin method (h(2)). The anthropometric measures and somatotype were assessed using standard validated procedures. Significant differences between monozygotic and dizygotic pairs of twins were found for height, endomorphy, ectomorphy, and mesomorphy, and the heritability for these measures was high (h(2) between 0.88 and 0.97). No significant differences were found between monozygotic and dizygotic twins for weight, and the BMI and the heritability indexes were lower for these measures (respectively 0.42 and 0.52). The results of the present study have indicated that the somatotype may be more sensible to genetic influences than the BMI in females.     

Twins and the paradox of dental-age estimations: A caution for researchers and clinicians

The biological age difference among twins is frequently an issue in studies of genetic influence on various dental features, particularly dental development. The timing of dental development is a crucial issue also for many clinicians and researchers. The aim of this study was therefore to verify within groups of twins how dental development differs, by applying Demirjian's method, Mincer's charts of development of third molars and two of Cameriere's methods for dental age estimation, which are among the most popular methods both in the clinical and the forensic scenario. The sample consisted of 64 twin pairs: 21 monozygotic, 30 dizygotic same-sex and 13 dizygotic opposite-sex with an age range between 5.8 and 22.6 years. Dental age was determined from radiographs using the mentioned methods. Results showed that dental age of monozygotic twins is not identical even if they share all their genes. The mean intra-pair difference of monozygotic pairs was low and similar to the difference in dizygotic same-sex twins; the maximum difference between monozygotic twins, however, was surprisingly large (nearly two years). This should lead to some circumspection in the interpretation of systematic estimations of dental age both in the clinical and forensic scenario.     

Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies

Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10^-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10^-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.