India's Opportunities and Challenges in Establishing a Twin Registry: An Unexplored Human Resource for the World's Second-Most Populous Nation.

Nature and nurture have always been a prerogative of evolutionary biologists. The environment's role in shaping an organism's phenotype has always intrigued us. Since the inception of humankind, twinning has existed with an unsettled parley on the contribution of nature (i.e. genetics) versus nurture (i.e. environment), which can influence the phenotypes. The study of twins measures the genetic contribution and that of the environmental influence for a particular trait, acting as a catalyst, fine-tuning the phenotypic trajectories. This is further evident because a number of human diseases show a spectrum of clinical manifestations with the same underlying molecular aberration. As of now, there is no definite way to conclude just from the genomic data the severity of a disease or even to predict who will get affected. This greatly justifies initiating a twin registry for a country as diverse and populated as India. There is an unmet need to set up a nationwide database to carefully curate the information on twins, serving as a valuable biorepository to study their overall susceptibility to disease. Establishing a twin registry is of paramount importance to harness the wealth of human information related to the biomedical, anthropological, cultural, social and economic significance.

The Value of Twins for Health and Medical Research: A Third of a Century of Progress.

In 1984, Hrubec and Robinette published what was arguably the first review of the role of twins in medical research. The authors acknowledged a growing distinction between two categories of twin studies: those aimed at assessing genetic contributions to disease and those aimed at assessing environmental contributions while controlling for genetic variation. They concluded with a brief section on recently founded twin registries that had begun to provide unprecedented access to twins for medical research. Here we offer an overview of the twin research that, in our estimation, best represents the field has progress since 1984. We start by summarizing what we know about twinning. We then focus on the value of twin study designs to differentiate between genetic and environmental influences on health and on emerging applications of twins in multiple areas of medical research. We finish by describing how twin registries and networks are accelerating twin research worldwide.

Associations between conduct problems in childhood and adverse outcomes in emerging adulthood: a longitudinal Swedish nationwide twin cohort.

BACKGROUND: We examined whether childhood conduct problems predicted a wide range of adverse outcomes in emerging adulthood and whether the association with internalizing problems remained after adjusting for general comorbidity and externalizing problems. METHODS: Participants were 18,649 twins from the Child and Adolescent Twin Study in Sweden. At age 9/12, parents rated their children on eight conduct problems. Adverse outcomes were retrieved from national registers in emerging adulthood (median follow-up time = 9.2 years), including diagnoses of six psychiatric disorders, prescriptions of antidepressants, suicide attempts, criminality, high school ineligibility, and social welfare recipiency. We estimated risk for the separate outcomes and examined if conduct problems predicted an internalizing factor above and beyond a general comorbidity and an externalizing factor. We used twin analyses to estimate genetic and environmental contributions to these associations. RESULTS: On the average, each additional conduct symptom in childhood was associated with a 32% increased risk of the adverse outcomes in emerging adulthood (mean hazard ratio = 1.32; range = 1.16, 1.56). A latent childhood conduct problems factor predicted the internalizing factor in emerging adulthood (ßboys  = .24, standard error, SE = 0.03; ßgirls  = .17, SE = 0.03), above and beyond its association with the externalizing (ßboys  = 0.21, SE = 0.04; ßgirls  = 0.17, SE = 0.05) and general factors (ßboys  = 0.45, SE = 0.03; ßgirls  = 0.34, SE = 0.04). These associations were differentially influenced by genetic and environmental factors. CONCLUSIONS: It is important to monitor boys and girls with conduct problems not only for future externalizing problems, but also for future internalizing problems. Prevention of specific outcomes, however, might require interventions at different levels.

An Update of Twin Research in Spain: The Murcia Twin Registry.

The Murcia Twin Registry (MTR) is the only population-based registry in Spain. Created in 2006, the registry has been growing more than a decade to become one of the references for twin research in the Mediterranean region. The MTR database currently comprises 3545 adult participants born between 1940 and 1977. It also holds a recently launched satellite registry of university students (N = 204). Along five waves of data collection, the registry has gathered questionnaire and anthropometric data, as well as biological samples. The MTR keeps its main research focus on health and health-related behaviors from a public health perspective. This includes lifestyle, health promotion, quality of life or environmental conditions. Future short-term development points to the expansion of the biobank and the continuation of the collection of longitudinal data.

Genetic Similarity Assessment of Twin-Family Populations by Custom-Designed Genotyping Array.

Twin registries often take part in large collaborative projects and are major contributors to genome-wide association (GWA) meta-analysis studies. In this article, we describe genotyping of twin-family populations from Australia, the Midwestern USA (Avera Twin Register), the Netherlands (Netherlands Twin Register), as well as a sample of mothers of twins from Nigeria to assess the extent, if any, of genetic differences between them. Genotyping in all cohorts was done using a custom-designed Illumina Global Screening Array (GSA), optimized to improve imputation quality for population-specific GWA studies. We investigated the degree of genetic similarity between the populations using several measures of population variation with genotype data generated from the GSA. Visualization of principal component analysis (PCA) revealed that the Australian, Dutch and Midwestern American populations exhibit negligible interpopulation stratification when compared to each other, to a reference European population and to globally distant populations. Estimations of fixation indices (FST values) between the Australian, Midwestern American and Netherlands populations suggest minimal genetic differentiation compared to the estimates between each population and a genetically distinct cohort (i.e., samples from Nigeria genotyped on GSA). Thus, results from this study demonstrate that genotype data from the Australian, Dutch and Midwestern American twin-family populations can be reasonably combined for joint-genetic analysis.

Inequality in genetic cancer risk suggests bad genes rather than bad luck.

Heritability is often estimated by decomposing the variance of a trait into genetic and other factors. Interpreting such variance decompositions, however, is not straightforward. In particular, there is an ongoing debate on the importance of genetic factors in cancer development, even though heritability estimates exist. Here we show that heritability estimates contain information on the distribution of absolute risk due to genetic differences. The approach relies on the assumptions underlying the conventional heritability of liability model. We also suggest a model unrelated to heritability estimates. By applying these strategies, we describe the distribution of absolute genetic risk for 15 common cancers. We highlight the considerable inequality in genetic risk of cancer using different metrics, e.g., the Gini Index and quantile ratios which are frequently used in economics. For all these cancers, the estimated inequality in genetic risk is larger than the inequality in income in the USA.

Validation of the Chinese version of Community Assessment of Psychic Experiences (CAPE) in an adolescent general population.

The Community Assessment of Psychic Experiences (CAPE) is a popular 42-item self-report assessment of psychosis proneness (PP) that has been widely-translated. However, there is as yet no validation of CAPE in non-Western languages. Here, we validated a Chinese translation of CAPE ("CAPE-C") in a young Chinese community sample. Factor analyses were employed in a sample of 660 individuals (mean age=18.63) to identify a culturally-sensitive factor structure for CAPE-C (Study 1). Since confirmatory factor analysis (CFA) suggested that CAPE-C did not follow the original factor structure, exploratory factor analysis and follow-up CFA were employed to establish an alternative structure, resulting in a 15-item "CAPE-C15" which retained a three-factor structure tapping positive, negative and depressive symptoms. To demonstrate the specificity of CAPE-C15 as a measure of PP, we conducted regression analyses to examine associations between CAPE-C15 dimensions and other measures of psychotic and depressive symptoms (Study 2). Results confirmed that CAPE-C15 dimensions showed specific associations with relevant symptom dimensions of other measures, but not with irrelevant ones. Finally, to aid interpretation of CAPE-C15 scores, Receiver Operating Characteristic analysis was conducted to establish a cut-off score that could indicate test-takers' need for clinical attention (Study 3). We found that a cut-off score of 8.18 on CAPE-C15 positive and negative symptom frequency and distress scores distinguished individuals whose PP was within normal ranges from those at psychometric high-risk (sensitivity: 78.6%; specificity: 77.7%). CAPE-C15 will likely prove relevant to researchers and healthcare providers who serve Chinese-speaking adolescents and young adults.

The 1966 Ciba Symposium on Transplantation Ethics: 50 Years Later.

In March 1966, the Ciba Foundation sponsored the first international, interdisciplinary symposium focused on ethical and legal issues in transplantation. The attendees included not only physicians and surgeons but also judges and legal scholars, a minister, and a science journalist. In this article, we will consider some of the topics in organ transplantation that were discussed by the attendees, what we have learned in the intervening half century, and the relevance of their discussions today. Specifically, we examine the definition of death and its implications for organ procurement, whether it is ethical and legal to "maim" a living individual for the benefit of another, how to ensure that the consent of the living donor is voluntary and informed, the case of identical twins, the question of whether ethically minors can serve as living donors, the health risks of living donation, the ethics and legality of an organ market, and the economic barriers to living donation. We show that many of the concerns discussed at the Ciba symposium remain highly relevant, and their discussions have helped to shape the ethical boundaries of organ transplantation today.

Multidimensional assessment of impulsivity in schizophrenia, bipolar disorder, and major depressive disorder: testing for shared endophenotypes.

BACKGROUND: Impulsivity is associated with bipolar disorder as a clinical feature during and between manic episodes and is considered a potential endophenotype for the disorder. Schizophrenia and major depressive disorder share substantial genetic overlap with bipolar disorder, and these two disorders have also been associated with elevations in impulsivity. However, little is known about the degree of overlap among these disorders in discrete subfacets of impulsivity and whether any overlap is purely phenotypic or due to shared genetic diathesis. METHOD: We focused on five subfacets of impulsivity: self-reported attentional, motor, and non-planning impulsivity, self-reported sensation seeking, and a behavioral measure of motor inhibition (stop signal reaction time; SSRT). We examined these facets within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic patterning in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420). RESULTS: We found evidence of moderate to high levels of heritability for all five subfacets. All three proband groups and their unaffected co-twins showed elevations on attentional, motor, and non-planning impulsivity. Schizophrenia probands (but not their co-twins) showed significantly lower sensation seeking, and schizophrenia and bipolar disorder probands (but not in their co-twins) had significantly longer SSRTs, compared with healthy controls and the other groups. CONCLUSIONS: Attentional, motor, and non-planning impulsivity emerged as potential shared endophenotypes for the three disorders, whereas sensation seeking and SSRT were associated with phenotypic affection but not genetic loading for these disorders.

A Comparison of Disease Burden Between Twins and Control Pairs in Medicare: Quantification of Heredity's Role in Human Health.

To quantify heredity's effects on the burden of illness in the Medicare population, this study linked information between participants in a research twin registry to a comprehensive set of Medicare claims. To calculate disease categories, the authors used the Centers for Medicare & Medicaid Services Hierarchical Conditions Categories (HCC) model that was developed to risk adjust Medicare's capitation payments to private health care plans based on the health expenditure risk of their enrollees. Using the Medicare database, 2 sets of unrelated but demographically matched control pairs (MCPs) were generated, one specific for the monozygotic twin population and the second specific for the dizygotic twin population. The concordance and correlation rates of the 70 HCC categories for the 2 twin populations, in comparison to their corresponding MCP, was then calculated using Medicare claims data from 1991 through 2011. When indicated, HCCs for which there was a statistically significant difference between the twin and corresponding MCP control group were analyzed by calculating concordance and correlation rates of the International Classification of Diseases, Ninth Revision codes that compose the HCC. Findings reveal that monozygotic twins share 6.5% more HCC disease categories than their MCP while dizygotic twins share 3.8% more HCC disease categories than their MCP. Atrial fibrillation is a highly heritable disease category, a finding consistent with prior literature describing the heritability of the cardiac arrhythmias. These findings are consistent with qualitative assessments of heredity's role found in previous models of population health, and provide both novel methods and quantitative evidence to support future model development.

The unmet concerns of twins with special needs: diagnostic challenges and service recommendations.

The quality of services provided to families of twins with special needs [SPNs] was examined in a US-based study. Participants included 30 parents with monozygotic (n=8) or dizygotic (n=22) twin pairs. Parents completed questionnaires containing quantitative and qualitative components addressing the circumstances and challenges surrounding their twins' diagnoses. Areas of unmet concerns included contact withother parents, respite care and grief counseling. Beneficial services included early interventions (e.g., occupational and physical therapy). Several resources were identified as not providing sufficient benefit (e.g., inadequate state resources). These findings underline the need to improve methods by which knowledge and support are disseminated to parents regarding diagnostic information and service availability. Practitioner and service recommendations are provided.

Living alongside more affluent neighbors predicts greater involvement in antisocial behavior among low-income boys.

BACKGROUND: The creation of economically mixed communities has been proposed as one way to improve the life outcomes of children growing up in poverty. However, whether low-income children benefit from living alongside more affluent neighbors is unknown. METHOD: Prospectively gathered data on over 1,600 children from the Environmental Risk (E-Risk) Longitudinal Twin Study living in urban environments is used to test whether living alongside more affluent neighbors (measured via high-resolution geo-spatial indices) predicts low-income children's antisocial behavior (reported by mothers and teachers at the ages of 5, 7, 10, and 12). RESULTS: Results indicated that low-income boys (but not girls) surrounded by more affluent neighbors had higher levels of antisocial behavior than their peers embedded in concentrated poverty. The negative effect of growing up alongside more affluent neighbors on low-income boys' antisocial behavior held across childhood and after controlling for key neighborhood and family-level factors. CONCLUSIONS: Findings suggest that efforts to create more economically mixed communities for children, if not properly supported, may have iatrogenic effects on boys' antisocial behavior.

Multiple births in sub-saharan Africa: epidemiology, postnatal survival, and growth pattern.

The study endeavored to assess the epidemiology, postnatal survival, and growth pattern of multiple births in Sub-Saharan Africa (SSA). It was based on the data of 25 demographic health surveys conducted in the subcontinent since 2008. The records of 213,889 children born in the preceding 59 months of the surveys were included. The multiple birth rate was computed as the number of multiple confinements per 1,000 births. Factors associated with multiple births were identified using logistic regression and their survival pattern was assessed using the Kaplan-Meier method. The multiple birth rate was 17.1 (95% confidence interval: 17.7-16.6) and showed considerable variation across the 25 countries included in the study. Odds of multiple births were significantly increased with advanced maternal age, parity, and maternal height but not with wealth index, age at first birth, and month of birth. At the end of the fourth year of age, the cumulative survival probability was as low as 0.77 in multiple births as compared to 0.93 in their counterparts. The odds of neonatal, infant and under-five mortality were 5.55, 4.39, and 3.72 times increased in multiple births, respectively. Multiple births tend to be malnourished than singletons and the odds of wasting, stunting, and underweight were 1.31, 1.83, and 1.73 times raised, consecutively. Nevertheless, multiple births regain their weight-for-age (WFA) and height-for-age (HFA) deficits by the end of the fourth year of age. Counseling pregnant mothers with multiple gestation to give birth at a health institution and providing close medical follow-up during and after the neonatal period can improve the survival of multiple births.

The causal nature of the association between neighborhood deprivation and drug abuse: a prospective national Swedish co-relative control study.

BACKGROUND: Risk for drug abuse (DA) is strongly associated with neighborhood social deprivation (SD). However, the causal nature of this relationship is unclear. METHOD: Three Swedish population-based cohorts were followed up over 5 years for incident registration of DA in medical, legal or pharmacy records. In each cohort, we examined the SD-DA association, controlling carefully for individual socio-economic status (SES) with multiple measures, in the entire sample and among pairs of first cousins, paternal and maternal half-siblings, full siblings and monozygotic (MZ) twins discordant for SD exposure. The number of informative relative pairs ranged from 6366 to 166,208. RESULTS: In all cohorts, SD was prospectively related to risk for incident DA. In relative pairs discordant for SD exposure, the SD-DA association was similar to that seen in the entire population in cousins, half-siblings, full siblings and MZ twins. Eliminating subjects who were residentially unstable or had DA in the first two follow-up years did not alter this pattern. When divided by age, in the youngest groups, the SD-DA association was weaker in siblings than in the entire population. CONCLUSIONS: Across three cohorts, controlling for individual SES and confounding familial factors, SD prospectively predicted risk for incident DA registration. These results support the hypothesis that the SD-DA association is in part causal and unlikely to result entirely from personal attributes, which both increase risk for DA and cause selection into high SD environments. At least part of the SD-DA association arises because exposure to SD causes an increased risk of DA.

The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era veteran twins).

PURPOSE: To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans. METHODS: A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by the Composite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012. RESULTS: Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0 years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p < .001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size = 0.31 in theater and 0.47 in non-theater Veterans; p < .001 for both) and mental composite summary (MCS) (effect size = 0.99 in theater and 0.78 in non-theater Veterans; p < .001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size = 1.02 in theater and 0.96 in non-theater Veterans; p < .001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p < .05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings. CONCLUSIONS: Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.

Noninvasive twin zygosity assessment and aneuploidy detection by maternal plasma DNA sequencing.

OBJECTIVE: This study aimed to provide an individualized assessment of fetal trisomy 21 and trisomy 18 status for twin pregnancies by maternal plasma DNA sequencing. METHOD: Massively parallel sequencing was performed on the plasma/serum DNA libraries of eight twin pregnancies and 11 singleton pregnancies. The apparent fractional fetal DNA concentrations between genomic regions were assessed to determine the zygosities of the twin pregnancies and to calculate the fetal DNA concentrations of each individual member of dizygotic twin pairs. Z-scores were determined for the detection of trisomy 18 and trisomy 21. RESULTS: Circulating DNA sequencing showed elevated chromosome 21 representation in one set of twins and elevated chromosome 18 representation in another pair of twins. Apparent fractional fetal DNA concentration analysis revealed both sets of twins to be dizygotic. The fractional fetal DNA concentrations for each individual fetus of the dizygotic twin pregnancies were determined. Incorporating the information about the fetal DNA fraction, we ascertained that each fetus contributed adequate amounts of DNA into the maternal circulation for the aneuploidy test result to be interpreted with confidence. CONCLUSION: Noninvasive prenatal assessment of fetal chromosomal aneuploidy for twin pregnancies can be achieved with the use of massively parallel sequencing of cell-free DNA in maternal blood.

Quantitative genetic research on sleep: a review of normal sleep, sleep disturbances and associated emotional, behavioural, and health-related difficulties.

Over the past 50 years, well over 100 twin studies have focussed on understanding factors contributing to variability in normal sleep-wake characteristics and sleep disturbances. Whilst we have gained a great deal from these studies, there is still much to be learnt. Twin studies can be used in multiple ways to answer questions beyond simply estimating heritability. This paper provides a comprehensive review of some of the most important findings from twin studies relating to sleep to date, with a focus on studies investigating genetic and environmental influences contributing to i) objective and subjective measures of normal sleep characteristics (e.g., sleep stage organisation, sleep quality); as well as sleep disturbances and disorders such as dyssomnias (e.g., insomnia, narcolepsy) and parasomnias (e.g., sleepwalking, bruxism); ii) the persistence of sleep problems from childhood to adulthood, and the possibility that the aetiological influences on sleep change with age; iii) the associations between sleep disturbances, emotional, behavioural and health-related problems; and iv) processes of gene-environment correlation and interaction. We highlight avenues for further research, emphasising the need to further consider the aetiology of longitudinal associations between sleep disturbances and psychopathology; the genetic and environmental overlap between sleep and numerous phenotypes; and processes of gene-environment interplay and epigenetics.