Background: Persistent high-risk human papillomavirus (HPV) infection is a necessary prerequisite for development of cervical cancer and its precursor lesion, high-grade squamous intraepithelial lesion (HSIL). However, HPV infection is not sufficient to drive this process, and genetic and environmental factors may also play a role. Methods/Design: The Cervical Cancer, Genetics and Environment Twin Study was established to investigate the environmental and genetic influences on variation in susceptibility to cervical pre-cancer in 25- to 69-year-old monozygotic (MZ) and dizygotic (DZ) twins recruited through the Australian Twin Registry. Reviews of Papanicolaou (Pap) screening histories were undertaken to identify individual women with a history of an abnormal Pap test. This was followed by detection of HPV in archival Pap smears of selected twin pairs to determine HPV persistence. Selected twin pairs also completed a detailed questionnaire on socio-demographic characteristics, sexual behavior, and HPV knowledge. In future analyses, under the assumptions of the classical twin design, case-wise concordance for persistent HPV infection and HSIL will be calculated for MZ and DZ twin pairs, and twin pairs (both MZ and DZ) who are discordant for the above outcomes will be used to assess the contributions of measured environmental risk factors. Discussion: The study examines factors related to HPV persistence and development of HSIL among female MZ and DZ twins. The results will contribute to our understanding of the natural history of cervical HPV infection and the relative contributions of genetic and environmental factors in disease progression.

Longitudinal studies of neuroticism have shown that, on average, neuroticism scores decrease from adolescence to adulthood. The heritability of neuroticism is estimated between 0.30 and 0.60 and does not seem to vary greatly as a function of age. Shared environmental effects are rarely reported. Less is known about the role of genetic and environmental influences on the rank order stability of neuroticism in the period from adolescence to adulthood. We studied the stability of neuroticism in a cohort sequential (classical) twin design, from adolescence (age 14 years) to young adulthood (age 32 years). A genetic simplex model that was fitted to the longitudinal neuroticism data showed that the genetic stability of neuroticism was relatively high (genetic correlations between adjacent age bins >0.9), and increased from adolescence to adulthood. Environmental stability was appreciably lower (environmental correlations between adjacent age bins were between 0.3 and 0.6). This low stability was largely due to age-specific environmental variance, which was dominated by measurement error. This attenuated the age-to-age environmental correlations. We constructed an environmental covariance matrix corrected for this error, under the strong assumption that all age-specific environmental variance is error variance. The environmental (co)variance matrix corrected for attenuation revealed highly stable environmental influences on neuroticism (correlations between adjacent age bins were between 0.7 and 0.9). Our results indicate that both genetic and environmental influences have enduring effects on individual differences in neuroticism.

The Interplay of Genes and Environment across Multiple Studies (IGEMS) is a consortium of 18 twin studies from 5 different countries (Sweden, Denmark, Finland, United States, and Australia) established to explore the nature of gene–environment (GE) interplay in functioning across the adult lifespan. Fifteen of the studies are longitudinal, with follow-up as long as 59 years after baseline. The combined data from over 76,000 participants aged 14–103 at intake (including over 10,000 monozygotic and over 17,000 dizygotic twin pairs) support two primary research emphases: (1) investigation of models of GE interplay of early life adversity, and social factors at micro and macro environmental levels and with diverse outcomes, including mortality, physical functioning and psychological functioning; and (2) improved understanding of risk and protective factors for dementia by incorporating unmeasured and measured genetic factors with a wide range of exposures measured in young adulthood, midlife and later life.

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

The NAS-NRC Twin Registry is one of the oldest, national population based-twin registries in the United States. It consists of 15,924 white male twin pairs born in the years 1917–1927 (inclusive) both of whom served in the armed forces. The registry, which has been in operation more than 30 years, has collected data from a variety of sources. Records-based, computerized data have come largely from the Department of Veterans Affairs, and there have been three major epidemiologic questionnaires, undertaken roughly every 15 years. Classic twin studies on a variety of medical conditions were the early focus of the registry, which now has a strong focus on chronic disease epidemiology. Work on a DNA specimen bank has been proceeding slowly, but is now a top priority, due to the increasing force of mortality in this twin cohort.

Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.

Proponents of the validity of the classical MZ-DZ twin comparison model for calculating heritability claim that the environments influencing MZ and DZ twin individuals are essentially identical. This ‘equal environments assumption’ may or may not be universally true when applied to the analysis of subjective traits. We examined the validity of this assumption as applied to the propensity for smoking cigarettes, reasoning that equality of environments should lead to equal smoking prevalences in MZ and DZ twin individuals. We identified 8 twin populations with data on smoking. We compiled odds ratios (ORs) for ever smoking in MZ and DZ twin individuals in these 8 studies and overall, using a fixed-effects meta-analytic method based on the Mantel-Haenszel procedure. The prevalence of smoking was less in MZ twin individuals than in DZ twin individuals in 7 of 8 studies. The overall OR was 0.86 (95% confidence interval 0.84, 0.89). ORs were virtually unchanged when the analyses were stratified for gender and age, and no differences were found in relation to the location of the study, the date of the study or the birth years of the cohorts. For cigarette smoking, the environments of MZ and DZ twins may not be co-equal. For subjective traits, heritability estimates may be influenced by these unequal environmental factors that differentially affect their development and characteristics in MZ and DZ twins.

Adolescents' evaluations of family functioning may have a significant impact on their subjective well-being and adjustment. The aim of the study was to investigate the degree to which genetic and environmental influences affect variation in evaluations of general family functioning, family conflict, and quality of life and the overlap between them. We assessed whether genetic and environmental influences are moderated by parental divorce by analyzing self-report data from 6,773 adolescent twins and their non-twin siblings. Genetic, shared, and nonshared environmental influences accounted for variation in general family functioning and family conflict, with genetic influences being relatively more important in girls than boys in general family functioning. Genetic and nonshared environmental influences accounted for variation in quality of life, with genetic influences being relatively more important in girls. Evidence was found for interaction between genetic factors and parental divorce: genetic influence on general family functioning was larger in participants from divorced families. The overlap between general family functioning and quality of life, and family conflict and quality of life was accounted for the largest part by genetic effects, with nonshared environmental effects accounting for the remaining part. By examining the data from monozygotic twins, we found evidence for interaction between genotype and nonshared, non-measured, environmental influences on evaluations of general family functioning, family conflict, and quality of life.

There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater in BRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15; p = 1.7 x 10-6) in BRCA1/2 families, with no evidence for interaction between tamoxifen therapy and BRCA1/2 genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members from BRCA1/2 families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk with BRCA1/2 mutation status alone.

The purpose of this article is to present alternative parameterizations of scalar and non-scalar sex-limitation models in the Mx matrix algebra program (Neale et al., 2002). These models are designed for use with extended pedigrees and take advantage of the dynamic treatment of covariates within Mx. Example scripts are provided.

The collection of papers in this special edition of Twin Research and Human Genetics represents a major land-mark at the intersection of behavioral genetics and political science. This issue is the fruit of 20 political scientists attending the Behavioral Genetics Association Methods Workshop in Boulder and a hands-on training practicum at the Virginia Institute for Psychiatric and Behavioral Genetics, and includes results from the first wave of political science twin surveys.

Most epidemiologic studies employ a vacuum cleaner used by a trained technician to collect household allergens. This approach is labor intensive, equipment dependent, and impractical if study subjects reside over a wide geographic area. We examined the feasibility of a self-administered dust collection method, using an electrostatic cloth sent by conventional mail, to obtain allergen measurements. Thirty-two nonasthmatic twins from the California Twin Program wiped areas in the family room, kitchen, and bedroom, according to standardized instructions, and returned the cloths by mail. Allergen concentrations for Der-p-1, Der-f-1, Fel-d-1, and Bla-g-2 were determined using ELISA, and intrahouse and room-to-room concentrations were compared. Der-p-1 and Fel-d-1 were found in most homes, with highest concentrations in bedrooms and kitchens, respectively. Der-f-1 and Bla-g-2 were rarely found. Intrahouse Der-p-1 and Fel-d-1 concentrations were highly correlated and statistically significant (for Der-p-1, bedroom vs. kitchen, p = .0003, bedroom vs. family room, p = .0001, and family room vs. kitchen, p = .002; for Fel-d-1, bedroom vs. kitchen, p = .0004, bedroom vs. family room, p < .0001, and family room vs. kitchen, p = .0001). Reported cat ownership was strongly correlated with household Fel-d-1 concentrations (p < .005). In another comparison from different homes of children enrolled in the La Casa atopy prevention study, allergen concentrations measured from dust collected by a single operator from the left and right half of the same room in 21 homes were compared. Levels of Bla-g-2, Der-p-1, and Fel-d-1 concentrations collected from right and left halves of the same room were highly correlated, with r2 ranging from .7 to .9, and were highly statistically significant (all p values < .01). We conclude that nonintrusive and self-administered dust collection, using commercially available electrostatic dust cloths, sent by conventional mail services, is a promising alternative to technician-collected vacuumed dust for measuring indoor allergens in population-based studies, although further validation of the method is necessary.

The population-based Northern Survey of Twin and Multiple Pregnancy (NorSTAMP, formerly the Multiple Pregnancy Register) has collected data since 1998 on all multiple pregnancies in North of England (UK) from the earliest point of ascertainment in pregnancy. This paper updates recent developments to the NorSTAMP and presents some early mortality data from the first 10 years of data collection (1998–2007). Since 2005, mothers have been asked to give explicit consent for their identifiable data to be held by the survey, in line with changing guidance and legal frameworks for identifiable data. In 2009, regional standards of care for multiple pregnancies were developed, agreed, and disseminated. During 1998–2007, 4,865 twin maternities (pregnancies with at least one live birth or stillbirth) were registered, with an average twinning rate of 14.9 per 1,000 maternities. The overall stillbirth and neonatal mortality rates in twins were 18.0/1,000 births and 23.0/1,000 live births respectively. Stillbirth and neonatal mortality rates were significantly higher in monochorionic than dichorionic twins: 44.4 versus 12.2 per 1,000 births (relative risk [RR] 3.6, 95% Confidence Intervals [CI] 2.6–5.1), and 32.4 versus 21.4 per 1,000 live births (RR 1.5, 95% CI 1.04–2.2) respectively. There was no significant improvement during this period in either stillbirth or neonatal mortality rates in either chorionicity group. This population-based survey is an important source of data on multiple pregnancies, which allows monitoring of trends in multiple birth rates and pregnancy losses, providing essential information to support improvements in clinical care and for epidemiological research.

New large-sample data show that non-additive genetic effects, probably epistatic interactions between loci, and sex-limited gene expression are significant features of the genetic architecture of human personality as measured by questionnaire scales of extraversion and neuroticism. Three large data sets – new data on large samples (n = 20 554) of US twins, their spouses, parents, siblings and children, correlations for Australian twins (n = 7 532), and previously published twin data from Finland (n = 14 288) – are subjected to an integrated analysis to test alternative hypotheses about the genetic causes of family resemblance in personality. When allowance is made for differences in reliability of the scales, the combined data are consistent with the same model for variation. There are significant amounts of genetic non-additivity for both dimensions of personality. The evidence favours additive × additive epistatic interactions rather than dominance. In the case of neuroticism, there is especially strong evidence of sex differences in genetic architecture favouring a greater relative contribution of non-additive genetic effects in males. The data confirm previous claims to find no major contribution of the shared environment of twins and siblings to these dimensions of personality. Correlations between spouses are zero, and the correlations for very large samples of siblings and non-identical twins do not differ significantly.

Objective: Routine obstetric ultrasound increasingly leads to the detection of structural fetal anomalies. In twin pregnancies with one anomalous twin, counseling on management strategies is complicated. Patients and methods: Twin pregnancies (n = 212) were referred to a tertiary center between January 2007 and July 2009. In a retrospective analysis, twins discordant for a structural fetal anomaly were compared to twins without anomalies in the prenatal ultrasound. Outcome parameters were survival and gestational age at birth. Results: Anomalies were seen in at least one fetus of 30 twin pairs. The two pregnancies in which the anomalies were concordant were terminated. Selective feticide was performed in three cases of major but non-lethal anomalies in dichorionic twins. The remaining 25 cases were managed expectantly. In three of these cases, spontaneous fetal demise of the affected fetus was observed. In five cases with major (lethal) anomalies, the pregnant women and their partners opted for non-intervention comfort care after birth for the affected fetus. Median gestational age at delivery was 257 days for twins without structural anomalies and was 254 days (n = 22) for twins with one anomalous fetus. This was not significantly different (Mann Whitney U, p = .69). Again, no difference was found for median gestational age at delivery in normal vs. discordant anomalous dichorionic twins if subdivided for chorionicity (Mann Whitney U, p = .68). Conclusion: In this cohort we describe the request for expectant management by pregnant women and their partners of those twins discordant for major (lethal) anomalies. Expectant management was not associated with increased risk of premature delivery. Fetocide was only opted for in a small number of cases with severe but non-lethal anomalies in dichorionic twins.

Risk factors for coronary heart disease (CHD), including prethrombotic changes in hemostasis, cluster with the insulin resistance (IR) syndrome. The aim of the present study was to investigate to what extent the relation between IR and hemostatic risk factors is due to shared genes or environmental factors. Multivariate genetic analysis was performed using a total of 314 (107 monozygotic and 207 dizygotic) twin pairs on IR assessed by HOMA, fibrinogen, plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (tPA), factor VIII (FVIII), von Willebrand factor (vWF) and factor XIII Bsubunit. The relationship between IR and the 6 hemostatic factors could best be explained by an independent pathway model consisting of 2 common genetic factors, one of which influenced IR and all hemostatic factors, and 3 common environmental factors, each representing the shared variance between IR and different aspects of the hemostatic system. Genetic correlations between IR and hemostatic proteins were larger than their environmental counterparts. Since IR and prethrombotic changes are features of both diabetes and CHD, the finding of one set of pleiotropic genes warrants the identification of these common pathways which may provide new avenues for treatment and prevention of both diabetes and CHD.

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

The management of twin pregnancies discordant for trisomy 21 is dependent on the gestation at diagnosis, chorionicity, and parental preference. Our experience with the management of 15 cases in 1,839 twin pregnancies over a 12-year period is described. Selective termination is not always associated with a successful outcome for the normal co-twin. Two of the three monochorionic twin pregnancies affected by trisomy 21 were discordant. Amniocentesis should be strongly considered rather than chorionic villus sampling in monochorionic twin pregnancies. Pregnancies that continue with a trisomy 21 affected fetus are at risk of polyhydramnios and premature labor.

The objective was to examine the association between several obesity-related nongenetic behaviors and body mass index (BMI) and waist circumference (WC) in young adult twins using reports from both twins on their similarities and differences. A total of 713 monozygotic (MZ) and 698 same-sex dizygotic (DZ) twin pairs aged 22–28 years filled in structured questionnaires to compare their eating, physical activity and dieting behavior with their co-twin's behavior, and to report their own eating and exercise habits. In both MZ and DZ pairs, the co-twins for whom both twin pair members concordantly answered that this twin eats more, snacks more, eats more fatty foods and sweet and fatty delicacies, chooses less healthy foods, eats faster and exercises less, had significantly higher BMIs (0.6–2.9 kg/m2) and WCs (1.5–7.5 cm). Multivariate regression analysis identified co-twin differences in the amount of food consumed as the strongest independent predictor of intrapair differences in BMI (β = 0.63 and 1.21, for MZ and DZ, respectively, p < .001) and WC (β = 1.52 and 3.53, for MZ and DZ, respectively, p < .001). Higher leisure-time physical activity and healthier dietary choices clustered in the same subjects. The measurement of habitual dietary intake and physical activity has previously relied on subjective self-reports that are prone to misreporting. By using comparative measures within twin pairs we found that the amount of food consumed is the major contributor to obesity independent of genetic predisposition.

The Missouri Mothers and Their Children Study (MO-MATCH) was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record (BR) database. Interview and lab-based data were obtained from: (1) mothers of Missouri-born children (born 1998–2005), who smoked during one pregnancy but not during another pregnancy; (2) biological fathers when available; and (3) the children (i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP). This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre, peri, and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance used initiation.