Considerable progress continues to be made with regards to the value and use of disease associated polygenic scores (PGS). PGS aim to capture a person’s genetic liability to a condition, disease, or a trait, combining information across many risk variants and incorporating their effect sizes. They are already available for clinicians and consumers to order in Australasia. However, debate is ongoing over the readiness of this information for integration into clinical practice and population health. This position statement provides the viewpoint of the Human Genetics Society of Australasia (HGSA) regarding the clinical application of disease-associated PGS in both individual patients and population health. The statement details how PGS are calculated, highlights their breadth of possible application, and examines their current challenges and limitations. We consider fundamental lessons from Mendelian genetics and their continuing relevance to PGS, while also acknowledging the distinct elements of PGS. Use of PGS in practice should be evidence based, and the evidence for the associated benefit, while rapidly emerging, remains limited. Given that clinicians and consumers can already order PGS, their current limitations and key issues warrant consideration. PGS can be developed for most complex conditions and traits and can be used across multiple clinical settings and for population health. The HGSA’s view is that further evaluation, including regulatory, implementation and health system evaluation are required before PGS can be routinely implemented in the Australasian healthcare system.

Predictive relations between maternal variables and outcome status for 199 pairs of newborn twins were evaluated. The maternal independent variables included pregravid weight, weight at end of pregnancy, weight gain, age, parity, height, socioeconomic status, years of education, and body mass index. The twin dependent variables included birthweight, birth length, 5-min Apgar score, number of days in an isolette, number of days in the hospital, weight at discharge, and chronological age at discharge. For stepwise multiple linear regression analyses, the newborn twins were grouped by term (fullterm/preterm) and sex (female/male). A combination of a larger number of independent variables acted as statistically significant predictors of twin outcome for the preterm twins than for the fullterm twins, and for the male twins than for the female twins. This was noted particularly for the anthropometric variables and for parity. Maternal weight gain, typically considered to be the critical variable related to infant birthweight, consistently had a significant outcome role for the preterm twins and male twins, but not for the fullterm twins or female twins. Demographic variables had a low rate of prediction for newborn outcome. This study has demonstrated that evaluating twins within groups separated by potential risk variables allows for a more accurate description of the influence of maternal variables on twin outcome than evaluating twins across groups as a single population.

We sought to estimate levels of risk for stillbirth subtypes associated with twin gestations among pediatric mothers (10–14 years). Analysis was on twin pregnancies covering the period 1989 to 2000 in the United States. We classified stillbirth as term, preterm, small-for-gestational-age (SGA) or preterm-SGA. We then assessed the risks of these stillbirth subtypes in pediatric mothers using two comparison groups consisting of women aged 15 to 19 years old (adolescent mothers) and 20 to 24 years old (mature mothers). Adjusted risk estimates were by means of hazard ratios generated from a Cox proportional hazards regression model. We adjusted for dependence of observations within twin clusters using the robust sandwich estimator. The rate of stillbirth was highest among pediatric mothers (56/1000), followed by adolescent gravidas (29/1000) and lowest in mature mothers (20/1000; p for trend < .01). Overall, preterm stillbirth was the most frequent stillbirth phenotype while term stillbirth was the least frequent. Not a single case of term stillbirth was recorded in pediatric mothers. Among pediatric gravidas, the risk for preterm stillbirth was more than tripled (adjusted hazard ratio [AHR] = 3.4; 95% confidence interval [CI] = 2.5–4.6), and that of preterm-SGA stillbirth more than doubled (AHR = 2.6; 95% CI = 1.8–3.7) that of mature mothers respectively. The 30% risk elevation for SGA stillbirth among pediatric mothers was not found to be statistically significant (AHR = 1.1; 95% CI = 0.3–4.3). Pediatric motherhood is a risk factor for stillbirth in twin gestation, especially, preterm and preterm-SGA stillbirth phenotypes. Prevention of stillbirth among this category of mothers should target the period preceding full term.

There have been long questions about the relationship of schizophrenia to other mental disorders. Lifetime DSM-III-R diagnoses of mood and anxiety disorders in twins with clinically diagnosed schizophrenia (n = 24) and their non-affected co-twins (n = 24) were compared with twins from pairs without schizophrenia (n = 3327) using a sample from the Vietnam Era Twin Registry. Schizophrenic probands had significantly elevated rates of all included disorders (bipolar disorder, major depression, dysthymia, generalized anxiety disorder, panic disorder, and PTSD) compared with controls (P < 0.01). The odd ratios comparing co-twins of schizophrenic probands with controls was greater than three for every disorder, but did not attain statistical significance. A similar pattern was observed when analyses were restricted to only monozygotic twins (n = 12). Consistent with other studies, schizophrenics appeared to have higher rates of a range of mental disorders. Our results suggest that schizophrenia per se represents a risk factor for other psychiatric disorders, but the absence of significantly elevated risk among non-schizophrenic co-twins suggested that family environmental and/or genetic factors that contribute to risk of schizophrenia do not increase the risk of mood and anxiety disorders to the same extent that the risk of these other disorders is increased by the presence of schizophrenia. Twin Research (2000) 3, 28–32.

A discordant twin gestation, in which one fetus is significantly growth restricted, compared to the other normal twin, is a unique model that can be used to elucidate the mechanism(s) by which the intrauterine environment affects fetal growth. In many model systems, placental transcription factor genes regulate fetal growth. Transcription factors regulate growth through their activation or repression of downstream target genes that mediate important cell functions. The objective of this study was to determine the expression of the placental HLX homeobox gene transcription factor and its downstream target genes in dizygotic twins with growth discordance. In this cross-sectional study, HLX and its downstream target genes’ retinoblastoma 1 (RB1) and cyclin kinase D (CDKN1C) expression levels were determined in placentae obtained from dichorionic diamniotic twin pregnancies (n = 23) where one of the twins was growth restricted. Fetal growth restriction (FGR) was defined as small for gestational age with abnormal umbilical artery Doppler indices when compared with the normal control co-twin. Homeobox gene HLX expression was significantly decreased at both the mRNA and protein levels in FGR twin placentae compared with the normal control co-twin placentae (p < .05). Downstream target genes CDKN1C and RB1 were also significantly decreased and increased, respectively, at both the mRNA and protein levels in FGR twin placentae compared with normal control co-twin placentae (p < .05). Together, these observations suggest an important association between HLX transcription factor expression and abnormal human placental development in discordant twin pregnancies.

An impressive literature has revealed that variation in virtually every measurable phenotype is the result of a combination of genetic and environmental influences. Based on these findings, studies that fail to use genetically informed modeling strategies risk model misspecification and biased parameter estimates. Twin- and adoption-based research designs have frequently been used to overcome this limitation. Despite the many advantages of such approaches, many available datasets do not contain samples of twins, siblings or adoptees, making it impossible to utilize these modeling strategies. The current study proposes a measurement strategy for estimating the intergenerational transmission of antisocial behavior (ASB) within a nationally representative sample of singletons using an extended pedigree risk approach that relies on information from first- and second-degree relatives. An evaluation of this approach revealed a pattern of findings that directly aligned with studies examining ASB using more traditional twin- and adoption-based research designs. While the proposed pedigree risk approach is not capable of effectively isolating genetic and environmental influences, this overall alignment in results provides tentative evidence suggesting that the proposed pedigree risk measure effectively captures genetic influences. Future replication studies are necessary as this observation remains preliminary. Whenever possible, more traditional quantitative genetic methodologies should be favored, but the presented strategy remains a viable alternative for more limited samples.

Information on multiple deliveries with regard to Portugal is scarce. Based on data provided by the Portuguese Institute of Statistics (INE), the rates for double and triple deliveries were calculated since 1930. The results obtained show for twins a uniform temporal pattern up to the 1970s. At this time rates decreased, but later they gradually recovered, reaching their maximum level in 2010. For triplets, the highest rates occurred between 1999 and 2002. For the period 1988–2011, the rates of multiple deliveries were related to a set of variables recorded in the INE database on live births. Significant differences (p < .001) between simple and multiple deliveries were obtained for maternal age, parity and marital status. Considering the year when the delivery occurred, significant differences (p < .001) persisted for maternal age regardless of the year. For the type of mating, significance was consistently found since the year 2002 (either by using the marital or the cohabitation criteria), and for parity since 2003. With regard to territorial variation, throughout seven periods between 1930 and 2011, the rates among the 20 administrative Portuguese territories, including the two insular districts of Açores and Madeira, were mostly stable for twinning rates, with a minimum level in 1970–1989. Regarding triplets, the greatest inter-district variation was found after 1980. The results of the Portuguese study on multiple deliveries are interpreted in the context of the Iberian Peninsula based on findings reported for Spain.

Our objective was to determine whether chorionicity affects umbilical cord blood acid-base parameters of the second twin. This was a retrospective cohort of twin pregnancies delivered at ≥23 weeks of gestation at a tertiary hospital from 2010 to 2016. Patients were included if arterial and venous umbilical cord gas results were available for both newborns and chorionicity was confirmed histologically. Exclusion criteria included intrauterine fetal demise of either twin prior to labor, major fetal anomalies, monoamnionicity, uncertain chronicity and twin-to-twin transfusion syndrome. The primary outcome evaluated was the umbilical artery (UA) pH of the second twin. A total of 593 dichorionic (DC) and 86 monochorionic (MC) twin pregnancies were included. No difference in UA pH was observed between MC and DC twins. Among vaginal deliveries (n = 97), the UA pH of the first twin was higher than the second twin (7.26 vs. 7.24; p = .01). Twin-to-twin delivery interval (TTDI) ≥20 min was associated with a higher UA pH in the first twin compared to the second twin (7.25 vs. 7.16, respectively; p = .006). Multivariable logistic regression was used to predict arterial pH < 7.20 for the second twin; the most predictive factors were arterial pH < 7.20 for the first twin, chronic hypertension and prolonged TTDI. Chorionicity was not associated with any acid-base parameter of umbilical cord blood in either the first or second twin. No differences in neonatal outcomes were observed based on chorionicity or birth order. Populations with a lower cesarean delivery rate may yield different findings.

Twin research exploring genetic and environmental influences on athletic interests and talents is reviewed. Illustrative examples of twin athletes representing a variety of sports activities are presented. This is followed by an overview of twin studies offering critical insights into the onset and progress of leukemia. In the last section, timely events involving twins and parents of twins will be described — each case provides a new look at an old question.

The primary aim of the Guangzhou Twin Eye Study (GTES) is to explore the impact that genes and environmental influences have on common eye diseases. Since 2006, approximately 1300 pairs of twins, aged 7–15 years, were enrolled at baseline. Progressive phenotypes, such as cycloplegic refraction, axial length, height and weight, have been collected annually. Nonprogressive phenotypes such as parental refraction, corneal thickness, fundus photo, intraocular pressure and DNA were collected once at baseline. We are collaborating with fellow international twin researchers and psychologists to further explore links with general medical conditions. In this article, we review the history, major findings and future research directions for the GTES.

The mothers of 603 pairs of 3- to 13-year-old twins in Korea completed the Emotionality, Activity, Sociability (EAS) Temperament Survey and the Strengths and Difficulties Questionnaire in reference to their twins. Principal factor analysis of the seven scales comprising these measures yielded a general factor on which all the scales had moderate to large loadings. Univariate behavioral genetic analyses showed that individual differences on this general factor could best be accounted for by additive genetic and non-shared environmental effects, with a heritability of 53%. The results strengthen the construct validity of the general factor of personality (GFP) by extracting this higher-order dimension from disparate measures, and have implications regarding social desirability criticisms applied to the GFP theory.

While snus has been the focus of increasing public health interest, twin studies have examined neither sources of individual variation for its use nor the sources of resemblance between snus and cigarette use. Twins from the Norwegian Institute of Public Health Panel were assessed by self-report questionnaire for the initiation of regular use and maximal quantity used for snus and cigarettes. Twin modeling was performed using OpenMx on data from 2767 twins including 856 complete pairs. Fitting univariate twin models produced similar results for cigarette initiation and quantity with estimates of additive genetic, shared environmental and unique environmental effects of approximately 77%, 0% and 23%, respectively. Estimates of snus initiation and quantity were, respectively, approximately 53%, 26% and 21%. Joint analyses suggested that the genetic, shared environmental and unique environmental correlations between cigarette and snus initiation and quantity were +.82, 0 and +.42, respectively. However, these results could not be statistically distinguished from a model which postulated that resemblance between cigarette initiation and quantity resulted from genetic and unique environmental correlations of +.47 and +.43. Compared with cigarette initiation and quantity of use in Norwegian twins, the role of genes was less prominent and shared environment more prominent for initiation and quantity of use of snus. Joint analyses of both tobacco phenotypes suggested, but did not confirm definitively, that genetic risk factors for cigarette and snus use were similar but not identical, while shared environmental factors existed that were specific to snus use.

This case study examined the hypothesis that longer outdoor time results in normal vision and refractive status, using unique genetically informative kinships. The participants were the members of 29-year-old doubly exchanged monozygotic male twin pairs from Bogotá, Colombia, in South America. Comprehensive ophthalmological examinations, including uncorrected and corrected visual acuity, refraction and keratometry, and visual life history interviews were undertaken; all examinations were conducted by two ophthalmologists blind to the hypothesis, relatedness, and rearing status of the four participants. Normal uncorrected vision and refractive status were present in the two rural-raised, unrelated brothers, relative to their urban-raised counterparts. Uncorrected visual acuities were 20/160 and 20/200 for the city-raised twins and 20/20 and 20/30 for the country-raised twins. Premature birth, low birth weight, computer use, and reading time could not explain these differences. It was concluded that time spent outdoors appears to be a significant factor in the development of myopia, reinforcing extant findings via a novel experimental approach.

The twin children who survived the Holocaust and the horrific medical experiments conducted by Nazi doctors are sometimes overlooked in the relevant literature. This topic and more were discussed as part of an annual conference hosted by students from Yeshiva University's Medical Ethics Society in October 2012. A selective summary of this meeting is followed by summaries of recent twin studies concerning genetic influences on twinning, in vitro fertilization versus spontaneous twin pregnancies, gender identity disorder, and royal support for twin registries. Several human interest stories are also worth noting. They include identical twin school principals, twin loss at Sandy Hook Elementary School, timely twin documentaries, new twin and twin-like reunions, and the passing of two prominent twins.

The study is a critical analysis of the decisions to induce labour or schedule cesareans in the practice of a third level referral centre, with as outcome criterion the reduction of fetal death. 783 women pregnant with twins were included from 1.1.1993 to 31.12.1998, in three groups:originally booked, referred for care during pregnancy, or transferred from another institution. The results show that an important proportion of preterm deliveries result from a medical decision to induce labour or from a scheduled cesarean in the originally booked group with even higher proportions in groups of referred and transferred women. These results are discussed in relation to fetal death rates and causes. Deaths related to fetal growth restriction were not observed in women originally booked for care. The hospital bias has been discussed. The conclusion is that decisions to minimize fetal deaths in twin pregnancies increased preterm deliveries by medical decision.

Attention-deficit/hyperactivity disorder (ADHD) and obesity are positively associated, with increasing evidence that they share genetic risk factors. Our aim was to examine whether these findings apply to both types of ADHD symptoms for female and male adolescents. We used data from 791 girl and 735 boy twins ages 16−17 years to examine sex-specific phenotypic correlations between the presence of ADHD symptoms and overweight/obese status. For correlations exceeding .20, we then fit bivariate twin models to estimate the genetic and environmental correlations between the presence of ADHD symptoms and overweight/obese status. ADHD symptoms and height/weight were parent- and self-reported, respectively. Phenotypic correlations were .30 (girls) and .08 (boys) for inattention and overweight/obese status and .23 (girls) and .14 (boys) for hyperactivity/impulsivity and overweight/obese status. In girls, both types of ADHD symptoms and overweight/obese status were highly heritable, with unique environmental effects comprising the remaining variance. Furthermore, shared genetic effects explained most of the phenotypic correlations in girls. Results suggest that the positive association of both types of ADHD symptoms with obesity may be stronger in girls than boys. Further, in girls, these associations may stem primarily from shared genetic factors.

Dizygotic compared with monozygotic conceptions are at decreased risk of fetal and infant death and serious morbidity in surviving infants. Different sex twin maternities must be dizygotic but miscoding and incorrect registration of sex and number of fetuses may lead to an incorrect assignment of zygosity. The aim of the study was to validate the coding and registration of number and sex of births in multiple pregnancies. Fetal and infant death registrations from all multiple maternities in England and Wales 1993–1998 were examined. There were 51,792 twin, 1627 triplet and 51 higher order multiple maternities that were registered. Among these there were 1926 fetal deaths, 58 of which were registered as being of indeterminate sex but were coded as male in 56 and female in 2 cases. A fetus papyraceous was registered as male in 19 and as female in 19 cases. Other fetal deaths weighing ≤100g, with no mention of papyraceous on the death certificate, nevertheless, likely to be of indeterminate sex, were registered as male in 26 and as female in 23 cases. In 13 maternities, the number of infants registered at birth was less than the number mentioned on the registration certificate. It cannot be assumed that multiple births of different registered sex are dizygotic. As surviving infants from a monozygotic multiple birth are at much greater risk of infant death and serious morbidity than dizygotic multiple births, incorrect assignment of sex has important implications for parental counselling and may have medicolegal relevance when attributing negligence as the cause of morbidity in a survivor from a multiple pregnancy.

Monozygotic (MZ) twins spend more time with each other and are more genetically alike than are dizygotic (DZ) twins or nontwin siblings and therefore probably experience less diversity in their playmates than DZ twins, who in turn may experience less diversity than other-age siblings. Thus MZ twins may be more inhibited than DZ twins, who may in turn be more inhibited than nontwin siblings. To test this, 205 children (42 MZ twins, 94 DZ twins, and 69 nontwin siblings) were assessed in a playroom laboratory during free play with an unfamiliar peer. Children's inhibition was rated based on latency to touch a toy for the first time and amount of time spent interacting with the other child. Additionally, the Child Behavior Checklist (CBCL) withdrawn scale was used to assess inhibition according to parent report. Behavioral ratings showed that MZ and DZ twins did not significantly differ on the inhibition or withdrawn ratings. DZ twins were significantly more inhibited than were nontwin siblings, according to laboratory ratings. Greater inhibition of twins during the free peer play situation can be explained by their relative lack of experience in playing with children who are less genetically and phenotypically like themselves. Parental ratings showed exactly the opposite pattern, suggesting a rater bias effect.

Some, albeit not all studies on the relationship between intrauterine growth retardation (IUGR) and female pubertal development have found an earlier and rapidly progressing puberty as well as concomitant disorders of related functional systems such as polycystic ovary syndrome and short stature. These pubertal changes are part of a growing list of IUGR-related diseases, which includes non-insulin dependent diabetes mellitus and coronary heart disease. A pulsatile release of gonadotropin releasing hormone is thought to be a conditio-sinne-qua-non for the initiation of puberty. In the absence of prospective studies on gonadotropin releasing hormone pulse patterns in IUGR-children other markers of pubertal development such as age at menarche have been deployed. From these studies it is not clear, however, whether the findings of an earlier onset of puberty in IUGR-girls merely reflect a more rapid progression of puberty. Both the role for IUGR and the mechanisms behind the onset of puberty are still elusive. Assuming a connection between IUGR and pubertal development, parallels can be drawn between hypotheses on the longterm consequences of IUGR and hypotheses on the initiation of puberty. For example, the somatometer concept proposes a role for fat mass in the initiation of puberty, which is compatible with the hypothesis on non-skeletal catch-up growth after IUGR. The debate on the origins of puberty and the role of IUGR mainly focuses on nature and nurture. Judgmentally, studies in mono- and dizygotic twins discordant for birth weight may be of particular help.

We seek to identify factors that facilitate or inhibit transmission of drug abuse (DA) from high-risk parents to their children. In 44,250 offspring of these parents, ascertained from a Swedish national sample for having a mother and/or father with DA, we explored, using Cox models, how the prevalence of DA was predicted by potentially malleable risk factors in these high-risk parents, their spouses and the rearing environment they provided. Analyses of offspring of discordant high-risk siblings and offspring of discordant sibling-in-laws and step-parents aided causal inference. Risk for DA in the children was associated with high-risk and married-in parental externalizing psychopathology, a range of other features of these parents (e.g., low education and receipt of welfare), and aspects of the rearing environment (e.g., neighborhood deprivation and number of nearby drug dealers). Offspring of discordant high-risk siblings, siblings-in-laws and step-parents suggested that nearly all these associations were partly causal. A multivariate analysis utilizing offspring of discordant high-risk siblings identified the six most significant potentially malleable risk factors for offspring DA: (1) criminal behavior (CB) in married-in parent, (2) community peer deviance, (3) broken family, (4) DA in high-risk parent, (5) CB in high-risk parent and (6) number of family moves. Children in the lowest decile of risk had a 50% reduction in their DA prevalence, similar to that seen in the general population. We conclude that transmission of DA from high-risk parents to children partly results from a range of potentially malleable risk factors that could serve as foci for intervention.