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.     

Paternal familial twinning: hypothesis and genetic/medical implications.

The phenomenon of paternally dependent familial twinning has been known in human and animal genetics since the 1920s, but still remains without any theoretical explanation and is indeed a neglected field of inquiry. Over the last two decades investigations in reproduction biology have discovered the significant role of multiple paternally dependent errors in fertilization including androgenic triploidy and moles. We suggest the hypothesis that the fathers of twins in the relevant families carry gene variants that increase the probability of dispermy, diplospermy and male pronucleus heterochrony as well as involvement of two male pronuclei in the fertilization of two female meiotic products. Any resulting twins would be an exceptional intermediate between MZ and DZ twins - and might properly be described as "sesquizygotic" (SZ). Paternal familial twinning may also go together with infertility due to triploidy, moles and chimerism. The hypothesis: (i) places the curiosities of paternally derived twinning within the framework of current knowledge of reproductive genetics and verifiable phenomena; (ii) predicts the existence of families in which twinning is associated with reproductive abnormalities; (iii) predicts an occurrence in relevant families of the third and intermediate category of SZ twins. Families with paternal twinning may thus provide the natural selective system for the search of unusual cases of primary chimeras, the frequency of which is still unknown.     

Hydatidiform mole: genetic origin in polyploid conceptuses

Summary The origin of 29 polyploid conceptuses with villous cystic swelling was examined. One tetraploid specimen showed one maternal and three paternal contributions to the genome. Informative cytogenetic markers in 24 triploids were consistent with fertilization by dispermy. Analysis of cytogenetic markers indicated that polyspermy may account for essentially all polyploid conceptions with an excess of paternal to maternal chromosome complements. The origin of the genome was primarily demonstrated by the study of cytogenetic markers, while HLA determination and enzyme analysis were less informative.     

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.     

Twinning in a colony of vervet monkeys (Cercopithecus aethiops sabaeus)

From 1975 through 1991, three sets of twins were born from a total of 693 live and stillborn births (0.43%) at the UCLA/Sepulveda Veterans Administration Medical Center Nonhuman Primate Research Laboratory, CA. None of the twin's mothers were related. Positive patrilineal relationships have not been established; however, a brother (not a twin) of the first set of twins may have fathered the third set. All twins were born to multiparous females and, in each case, only one infant survived beyond 4 days. One set of twins was dizygotic; the genetic status of the others is unknown. © 1994 Wiley-Liss, Inc.     

Paternally inherited alleles in male body parts of an ant (<Emphasis Type="Italic">Diacamma</Emphasis> sp.) sex mosaic: implication for androgenetic male production in the Hymenoptera

Sex mosaicism, also called gynandromorphism, refers to an accidental phenomenon in dioecious organisms (mainly animals) in which an individual phenotype includes both female and male characteristics. Despite the rarity of this phenomenon, elucidating the mechanisms of naturally occurring sex mosaicism should deepen our understanding of diverse sex determination and differentiation systems in nature. We report the results of a genetic study of a sex mosaic individual of the ant Diacamma sp. from Japan’s Okinawa Island. Parentage analysis using microsatellite markers revealed that the female and male parts of the sex mosaic showed different inheritance patterns: female parts had alleles consistent with their biparental inheritance, whereas most of the male parts had alleles consistent with their paternal inheritance (i.e., androgenesis). We discuss plausible cytogenetic mechanisms that gave rise to the male parts of this individual: polyspermy and the subsequent independent cleavage by a surplus sperm pronucleus, and maternal genome elimination after fertilization of an ovule. Moreover, we hypothesize that the androgenetically produced males found in some Hymenoptera might share the same underlying cytogenetic mechanism with hymenopteran sex mosaicism.     

Contribution of hereditary factors to the variability of growth at different stages of individual development (twin studies)

A study of monozygotic and dizygotic twins from the moment of their birth till 13 years of age showed that differences in twin genesis and conditions of prenatal development exert no statistically significant influence on formation of average indices. At different stages of ontogenesis contribution of the genetic determinant estimated by index H was different as to a degree of manifestation, directivity (+; -) sex-dependent peculiarities of realization.     

No paternal effect on monozygotic twinning in the Swedish Twin Registry.

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.     

Paternal age and telomere length in twins: the germ stem cell selection paradigm

Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an ‘epigenetic’ mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age‐dependent germ stem cell selection process, whereby the selected stem cells have longer telomeres, are more homogenous with respect to telomere length, and share resistance to aging.     

Multiple birth and Down's disease]

The frequency of twinning among newborns with Down's syndrome (2,11+/-0,6%)was significantly higher than in the general populaltion (0,73+/-0,3%). The increase in the rate of multiple births of children with trisomy-21 occurred due to almost three-fold excess in the frequency of dizygotic (discordant) twin pairs over the expected level. The increase in the frequency of dizygotic twins with Down's syndrome was explained by the combined effect of two independent factors: the increase in probability of dizgotic twins natality and the enhanced rate of children birth with trisomy-21, which depended on the increase in mother's age.     

Monthly trend and seasonal variation in twinning rate in Japan, 1975–1994

We examined birth records from Japanese statistics, 1975–1994, to investigate the seasonality of twin births. We could identify 198 924 pairs of twins (97.9% of all the registered twin records) and estimated the numbers of mono- and dizygotic twin pairs. The seasonal index of the twinning rate for each month was calculated by dividing the crude rate by the estimated trend value for the month. There were significant variations in the seasonal index for overall, dizygotic and monozygotic twinning rates. Peak months with values more than 3% higher than expected were July and October–December for dizygotic twins, and April and June for monozygotic twins; these seasonalities were statistically significant by analysis of variance and the patterns were similar in recent years, with a sharp increase in the total twinning rate. When observed year-by-year, however, there were years that did not show these typical seasonalities. It is suggested that the mechanisms for probable seasonal variations in twinning rates are different for dizygotic and monozygotic twin pregnancies, and that factors involved in these variations are not effective every year. Received: 2 September 1998 / Revised: 6 May 1999 / Accepted: 26 May 1999     

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.     

Twins,triplets, and cerebral palsy in births in Western Australia in the 1980s.

OBJECTIVES--To examine the rate of cerebral palsy in twins and triplets in births from 1980 to 1989 in Western Australia and to identify factors associated with increase in risk. DESIGN--Pluralities for all births in Western Australia were identified through the standardised midwives'' notification system, and cases of cerebral palsy were identified from the Western Australian cerebral palsy register. MAIN OUTCOME MEASURES--Multiple births, cerebral palsy, excluding postneonatal cause. RESULTS--The prevalence of cerebral palsy in triplets, of 28 per 1000 survivors to 1 year (95% confidence interval 11 to 63) exceeded that in twins (7.3; 5.2 to 10) and singletons (1.6; 1.4 to 1.8). Although twins and triples were more likely than singletons to be low in birth weight, their risks of cerebral palsy if low in birth weight were similar. In contrast, in normal birthweight categories twins had a higher rate of cerebral palsy (4.2; 2.2 to 7.7) than singletons (1.1; 1.0 to 1.3). The prevalence of cerebral palsy was similar in twins of unlike sex pairs, all of whom are dizygotic, and in like sex pairs. A twin pair in which one member died in utero was at higher risk of cerebral palsy: 96 per 1000 twin pairs (36 to 218) compared with 12 (8.2 to 17) for twin pregnancies in which both survived. There was a similar but non-significant trend for death of one triplet to be associated with increased risk of cerebral palsy in the survivors of the set. CONCLUSION--Triplet pregnancies produced a child with cerebral palsy 47 times more often than singleton pregnancies did and twin pregnancies eight times more often. Eighty six per cent of cerebral palsy in multiple births was in twins. As multiple births are increasing mainly because of personal and medical decisions the increased risk of cerebral palsy in multiple births is of concern.     

The East Flanders Prospective Twin Survey (Belgium): a population-based register.

The East Flanders Prospective Twin Survey (EFPTS), started in 1964, is unique among the 17 major European twin registers because it is population based, the twins (and higher order births) are ascertained at birth, basic perinatal data are collected, chorion type is established and, when appropriate, genetic markers including DNA fingerprints, are determined. The total number of sets is 5089 twin, 158 triplet and 14 of higher order. Zygosity has been diagnosed on the basis of sex, placental structure and genetic markers in more than 95% of pairs. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early), the monochorionic-diamnionic pairs (intermediate), and the monochorionic-monoamnionic pairs (late). Methodology and basic results in twins are considered in this article; detailed studies will be reported later. The sex proportion in dizygotic (DZ) twins is the same as in singletons, whereas monozygotic (MZ) twins number more girls than boys. The difference in perinatal mortality between DZ and MZ twins is limited to the monochorionic MZ subgroup. Birth weight is highest in DZ twins and diminishes stepwise in MZ dichorionic and MZ monochorionic twins. Duration of pregnancy follows the same trend but is limited to a few days. Iatrogenic pregnancies are increasing to the point of representing almost 50% of the twin births in 1997.     

Fathering of Dizygotic Twins and Risk of Prostate Cancer: Nationwide,Population-Based Case-Control Study

Background

An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls.

Methods

We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden.

Results

1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89–1.02), nor for any risk category, OR 0.97 (95% CI 0.84–1.12) for low-risk disease, and OR 1.04 (95% CI 0.90–1.22) for metastatic disease.

Conclusion

The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.     

Menstrual characteristics of mothers of twins

The menarcheal age and frequency of menstrual disorders in mothers of dizygotic (DZ) and monozygotic (MZ) twins born in Denmark in 1984 or 1985 were compared with a control sample of mothers of singleton infants born in the same period. Compared to control mothers, mothers of DZ twins had a lower menarcheal age and a lower frequency of menstrual irregularities--menstrual cycles exceeding 5 weeks duration, varying length of menstrual cycles and episodes of menostasia. Mothers of MZ twins had a higher frequency of intermenstrual bleeding compared to mothers of singletons. All results were adjusted for maternal age and parity. The findings are relevant to the interpretation of aetiological factors leading to twin births and support the hypothesis of differences in sex hormone activity of the mothers of DZ twins in comparison with other women.     

New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.     

HLA haplotypes in dizygotic twin pairs: are dizygotic twins more similar than sibs?

It has been suggested that dizygotic twin pairs share two HLA haplotypes more often than ordinary siblings and thus might be genetically more alike. We tested this hypothesis in dizygotic twin pairs from the Danish Twin Registry. A total of 114 (60 female and 54 male) same-sexed healthy twin pairs aged 18-45 years participated. Dizygosity was established by means of DNA sequencing of nine polymorphic markers. HLA-A, B and Cw specificities were typed with serology, and if data were inconclusive, with DNA typing. If twin partners had the same HLA-types, they were assumed to share two haplotypes. If they had 1 HLA A, B and C antigen group in common they were assumed to share one haplotype and if they had no HLA types in common they were assumed to share zero haplotypes. Since HLA-types from parents were unavailable we could not test for identity-by-descent and thus had a risk of overestimating the number of twins sharing two haplotypes. A Chi-square test was used to compare observed numbers in each haplotype sharing group with the expected numbers. Twenty-nine (expected 28.5) twin pairs had two HLA-types in common, 52 (expected 57) had one HLA-type in common and 33 (expected 28.5) had zero HLA-types in common, p = 0.56. Our data show that DZ twins are not more similar than sibs from different pregnancies in general.