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The Study of Human Twins in Medical Research
Abstract
Identical and fraternal human twins are a unique resource for studies of the origin and natural history of various diseases, because their genetic similarities are well defined and easily understood. Most investigations using twins fall into two basic categories. In one, genetic factors that contribute to the cause of disease are assessed directly. In the other category, hereditary factors are excluded so that the etiologic importance of nongenetic factors can be evaluated in comparisons that control genetic variation. Both kinds of studies have helped to confirm or dispel specific hypotheses, have provided insights into disease processes, and have shed new light on the usefulness of this study population for future research. Laboratory and clinical investigators assign subjects randomly to different treatment groups to control and evaluate perturbations in their data that are due to factors not specifically accounted for in the study design. In studies on nonhuman subjects, littermates of inbred strains are often randomly assigned to treatment groups to reduce as much as possible the extraneous effects of genetic and early environmental factors. Research on human beings must accommodate a number of constraints: human beings are genetically heterogeneous; they may not be assigned to potentially harmful treatments; and they cannot be assigned at random in studies of spontaneously occurring outcomes, such as diseases of unknown cause. Human twins, however, provide opportunities for evaluating genetic and environmental factors in pairs of subjects of the same age who are either genetically identical or closely related and who have usually shared a common family background and many childhood environmental exposures and experiences.
... Some twin models are well suited to studies that seek to differentiate between cause and association in human health (reviewed in Hrubec & Robinette, 1984;and van Dongen et al., 2012). Their sensitivity stems from the unique capacity of twin designs, especially the MZ co-twin design, to control for variables that often confound population studies. ...
... Once an infection appears in the amniotic sac of one twin, layers of amnionand in dichorionic twins, of chorion, in addition to the co-twin's placentacould protect the co-twin from its spread. Hrubec and Robinette (1984) reported that MZ co-twin studies had already revealed associations linking low birth weight with cerebral palsy as well as schizophrenia. Since then, studies using this design have found associations linking higher birth weight with cognition in very early childhood (Halling et al., 2015) and with higher BMI in adolescence and adulthood (Pietilainen et al., 2002), as well as associations linking lower birth weight with higher blood pressure in childhood (Dwyer et al., 1999), with early onset of puberty (Schulte et al., 2016) and with risk of type 2 diabetes in adulthood (Poulsen et al., 1997). ...
... To date, researchers with CODATwins have found that DZ twins in childhood are taller and have higher BMI than MZ twins , that genetic factors play a major role in the variation of BMI among adolescent populations of different ethnicities exposed to different obesogenic factors (Silventoinen et al., 2016) and that first-born twins are slightly taller and have higher BMI than their second-born co-twins . Finally, the 'Mothers of Twins Clubs' cited by Hrubec and Robinette (1984) as a key resource to identify twins for research engagement have since evolved into multiple birth associations established across the world, with global representation through the International Council of Multiple Birth Organisations. ...
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.
... Twins have participated in medical research for more than a century (Boomsma et al., 2002;Craig et al., 2020;Hrubec & Robinette, 1984;Martin et al., 1997). Previous reviews have highlighted the unique role twins play in understanding genetic and environmental contributions to disease and have provided many examples of the valuable contribution twin studies have made to medical research (Craig et al., 2020;Hrubec & Robinette, 1984). ...
... Twins have participated in medical research for more than a century (Boomsma et al., 2002;Craig et al., 2020;Hrubec & Robinette, 1984;Martin et al., 1997). Previous reviews have highlighted the unique role twins play in understanding genetic and environmental contributions to disease and have provided many examples of the valuable contribution twin studies have made to medical research (Craig et al., 2020;Hrubec & Robinette, 1984). Studies in twins can be used to address questions of gene-environment interactions (Buil et al., 2015) and cause versus association (Sjölander et al., 2012) and have been used in modern specialist areas of medical science such as epigenetics (Bell & Saffery, 2012), stem cells (Hibaoui et al., 2014) and microbiome research (Smith et al., 2013). ...
Although twins often participate in medical research, few clinical trials are conducted entirely in twin populations. The purpose of this review is to demonstrate the substantial benefits and address the key challenges of conducting clinical trials in twin populations, or ‘twin-only trials’. We consider the unique design, analysis, recruitment and ethical issues that arise in such trials. In particular, we describe the different approaches available for randomizing twin pairs, highlight the similarity or correlation that exists between outcomes of twins, and discuss the impact of this correlation on sample size calculations and statistical analysis methods for estimating treatment effects. We also consider the role of both monozygotic and dizygotic twins for studying variation in outcomes, the factors that may affect recruitment of twins, and the ethics of conducting trials entirely in twin populations. The advantages and disadvantages of conducting twin-only trials are also discussed. Finally, we recommend that twin-only trials should be considered more often.
... Twins were classified as MZ or DZ according to their self-reports, assuming their accuracy up to 5% based on previous investigations [9]. Actual body weight and height were measured with the use of standard anthropometric methods. ...
The purpose of the research was to assess the genetic and environmental influences on bone properties. One hundred thirty-two pairs of twins (99/33 monozygotic/dizygotic) underwent anthropometric measurements and phalangeal quantitative ultrasound (DBM Sonic 1200, Igea, Italy) measuring the amplitude speed of sound (AD-SoS, m/s). The mean age was 16.78 ± 12.35 years for monozygotic twins and 14.30 ± 8 years for dizygotic. Interpair and intrapair correlations between twins were calculated. In the groups of monozygotic and dizygotic twins, Ad-SoS correlated significantly with age (r = 0.56–0.73, p < 0.05), weight (r = 0.73–0.78, p < 0.05), and height (r = 0.80–0.81, p < 0.05). The strongest intrapair correlation (r = 0.99–0.998) was noted in monozygotic females for Ad-SoS, weight, and height. There was a statistically significant correlation between the intrapair difference of Ad-SoS and age but only in the groups of monozygotic and dizygotic females (r = 0.281, r2 = 0.079, and p = 0.028; r = 0.544, r2 = 0.296, and p = 0.01, respectively). After age adjustment, it was estimated that 28.62% of Ad-SoS in women and 13.2% of Ad-SoS in men was explained by genetic influence, leading to the conclusion that Ad-SoS changed with age, weight, and height. The strongest correlation between pairs of twins was observed in monozygotic twins. The differences in bone values between female twins arose with age, which indicated the role of environmental factors.
... Multiple pregnancy accounts for 1.5% of all pregnancies among these the development of the acardiac anomaly is a rare complication of monozygotic multiple pregnancies. 1 It was first described in the sixteenth century (Benedetti, 1533 and occurs in ~1% of monozygotic twin pregnancies and in 1 out of 35 000 deliveries. ...
Multifetal gestation is often a high-risk pregnancy and especially the monochorionic twin pregnancy significantly contributes to fetal morbidity and mortality. Acardiac twinning, earlier known as chorioangiopagus parasiticus, is the most extreme manifestation of this condition. An acardiac twin is a rare complication of multifetal pregnancy, in the literature reported at an incidence of 1% of monochorionic twin pregnancies, i.e. 1 of 35,000 pregnancies. Often results from abnormal placental vascular anastomoses. This leads to twin reversal arterial perfusion with complex pathophysiology. Here authors present a case of acardiac twin pregnancy presented at 26 weeks with the ultrasonography report suggested?? Placental teratoma of size 11×11×13 cm with polyhydramnios as there was no reason to suspect something else as the picture described in the USG report with the polyhydramnios was fitting with the diagnosis of placental teratoma but as the scan was done at taluka place and the images provided were not clear authors decided to confirm the diagnosis from fetal medicine specialist as MTP was not the option for the patient as she was 28 weeks who confirmed that as a case of acardiac twin pregnancy and the case was managed accordingly.
... Newly developed statistical techniques in multivariate modelling 14 and analysis of gene by environment interactions 15 provided extended uses of the classical and co-twin control method. Twin study designs had been classified into those investigating the genetic factors contributing to disease and those 'excluding', or adjusting for, genetic factors, thus useful to assess etiologic importance of environmental factors 16 , a distinction that is still reasonably clear in current approaches. ...
Twin studies enable powerful approaches for untangling the roles of genes and the environment on human traits and conditions. Twin registries have been established across the globe since the 1950’s to facilitate twin studies through collecting and maintaining data and contact information of twins. International scientific collaboration in twin research represents an opportunity for establishing a large pool of twin data and expertise for analysis. However, such collaborations are rare. The International Network of Twin Registries (INTR) has, so far, failed to deliver large multi-registry twin studies that can tackle big problems related to the health of the population.
I investigated the challenges of international scientific collaboration in twin research through a case study approach. To explore individual and interpersonal aspects of such challenges, I conducted 18 in-depth semi-structured interviews with researchers. To explore structural aspects, I studied the Brazilian Twin Registry (BTR), Twins Research Australia (TRA) and the INTR through participant observation. I also analysed documents, data reports and other information from the above case study sites. I found that these challenges can be grouped in three major themes: (1) the ‘silos’ in international twin research; (2) the capacity and the future sustainability of twin registries; and (3) ethical challenges in engagement, communication and policy-making.
Striking differences in resources between researchers and twin registries operating in the global arena of collaborative twin research appeared as substantial obstacles. My findings also suggest that twin research is currently divided into silos related to the researchers’ disciplines, personal motivations and belief systems. While such silos are not necessarily detrimental to scientific productivity within disciplines, they represent barriers to the large-scale international twin studies that can achieve sufficient sample sizes for robust study outcomes. More importantly, while most informants appeared confident in the capabilities of co-twin control studies, especially those with MZ twin pairs discordant for disease, many of them seemed to question the validity and clinical relevance of classical twin studies. Classical twin studies have continuously influenced public discussion and policy-making debates related to a variety of human traits and conditions for almost 100 years.
My findings have implications for the future of the BTR, TRA and, more broadly to other twin registries. They also contribute to possible future pathways for the INTR. However, the most significant contribution of my research pertains to how the misinterpretation of heritability estimates from classical twin studies by researchers and the media can lead to an agenda of genetic determinism. The confusion arising from the misleading communication of scientific findings from classical twin studies appeared as a major ethical challenge. These practices can also jeopardise the credibility of twin research as a tool to the understanding of the role of genes and the environment on human complex diseases. Researchers should take a proactive approach in helping educate the media, the public and policy-makers on what the findings from twin studies are really telling us, and perhaps even more importantly, what they are not.
... Regarding the assumptions underlying the use of concordance rates as a measure of genetic loading for homosexuality, it is commonly accepted that MZ and DZ twins have very similar environments. Yet evidence suggests that MZ twins may be genetically predisposed to select more similar environments than DZ twins (Hrubec & Robinette, 1984). In such a case, ratios of concordance rates in MZ and DZ twins will be biased by differences in population variability (Kendler, 1989). ...
Concurrent with an interest in the incidence and characterization of homosexuality has been an increased interest in the biological basis of such behavior. The present article reviews evidence in support of a biological basis of homosexuality in three interrelated categories—genetic evidence, the prenatal neurohormonal hypothesis, and neuroanatomical evidence. An attempt is made to not only review studies that are representative of experimental findings in each of these categories, but to critically assess the evidence in terms of experimental protocol. In an attempt to provide a Christian assessment of the biological evidence, three conclusions are drawn: (1) evidence for a biological basis of homosexuality is sufficient to warrant its acceptance; (2) the nature of the biological influence on homosexuality is predisposing not determining, thus providing the potential for change; and (3) acceptance of a biological basis of homosexuality in no manner changes the biblical condemnation or prohibition of such behavior. Finally, the need for the Christian church to reach out and minister to homosexual individuals is briefly discussed.
... Concordance rates of diseases with a substantial genetic component are expected to be significantly different in MZ compared to DZ twins (40). Different from classical twin studies, the co-twin control method is the best suited method to study the impact of specific genes or environmental risk factors on the development of disease (41). Twin pairs who are discordant for a given phenotype are considered as matched pairs and the healthy co-twin serves as a control for the affected twin. ...
p>Monozygotic twins share the same genotype since they are derived from the same zygote. However, monozygotic (MZ) twin siblings frequently present many phenotypic differences, such as their susceptibilities to diseases. These isogenic individuals are not entirely identical. They exhibit phenotypic incompatibility for many features, from birth weight to complex diseases. Recently, several studies have been published showing that phenotypic differences, especially in MZ twins, are being induced from prenatal period to life-long epigenetic differences. Epigenetic studies on twins have a great potential to contribute to our understanding of complex diseases, such as cancer, autoimmune disorders, psychiatric disorders and neurological diseases. Since MZ twins are genetic clones (genetically identical), they are considered as perfect models for studying the role of environmental factors as determinants of complex diseases and phenotypes. In this review, a number of intrauterine effects and genetic mechanisms that may affect phenotypic, genotypic, and epigenetic differences between MZ twins were described and effects of epigenetic mechanisms on complex diseases were mentioned. Further work on epigenetic changes in diseases using incompatible MZ twin models, would lead to new developments in medical therapies.</p
... Следует коснуться еще одной теории, основным положением которой является неравномерное распределение генетического материала между монозиготными плодами при многоплодной беременности, вследствие чего закладки сердца и внутренних органов не происходит [1]. Более того, существует мнение, что ряд ранее описанных тератом плаценты на самом деле являлись плодами-акардиусами с несформированными или нераспознанными пуповинами [14,15]. ...
Monochorionic multiple pregnancy has a higher risk for obstetric complications, including those due to the development of twin-To-Twin transfusion syndrome and reversed arterial perfusion syndrome (TRAP sequence). The latter occurs in 0.1% of all monochorionic pregnancies. The basis for TRAP sequence is a relationship between arterial and venous anastomoses from the appropriate placental areas, causing a recipient fetus to develop at the expense of a donor fetus. The presence of abnormal anastomoses is considered to be a main cause of acardia. The prognosis for a donor fetus is also unfavorable: The mortality rates in the absence of intrauterine correction are as high as 55%.
... Multiple pregnancy accounts for 1.5% of all pregnancies, with approximate perinatal morbidity and mortality of 10%. 1 Multiple pregnancy is complicated by congenital malformations twice as often as with singletons. Acephalus Acardia is extremely rare complication of multiple pregnancies and very uncommon congenital malformation disclosed in fetuses and newborns due to twin reverse arterial perfusion syndrome. ...
... Twin studies have added to the knowledge of human disease, by discriminating genetic or environmental etiology (Hrubec & Robinette, 1984). Twin research has survived criticisms on potential biases and the lack of population representativeness (Phillips, 1993). ...
The Korean Twin Registry is the first nationwide twin study in Korea. We compiled 154,783 twin pairs from existing nationwide data sources, mainly from address and national health insurance data. The coverage of this registry was almost complete for the twins born since 1970, but less complete as age increased, so that there were only 990 pairs who were born before 1930. The twins' health examination (N = 54,390 persons) and questionnaire (N = 44,546 persons) results were incorporated into the registry, yielding 12,894 and 9074 concordantly informative pairs. Morbidity and mortality outcomes have been followed up since 1990, for most diseases. For preliminary analysis of complex diseases, we selected ventricular septal defects (VSD) in young twins, stomach and colorectal cancers in adult twins. We identified 353 VSDs, 284 stomach cancers, and 116 colorectal cancers among twins. The prevalence rates of cancers, but not that of VSD, were lower in twins than those in population. The difference in the cancer prevalence was marked for twins born before 1926, implying some degree of selection. Like-sex (LS) twins showed familial recurrence risks (λLS) of 41.2 for VSD and 22.4 for colorectal cancers, and 1.74 for stomach cancers. For opposite-sex (OS) twins, we could estimate λOS of 19.8 for VSD only. These results were compatible with previous studies for VSD and colorectal cancers, but not for stomach cancers. Despite the strength in size, availability of health outcomes, and some lifestyle and basic laboratory data, we need accurate zygosity information to improve the validity of the results.
... This type of with twinning is associated with single umbilical artery: ~6 6% and underlying chromosomal anomaly: ~3 3% [5]. The other donor (pump) twin may develop cardiac failure (hydrops) with a reported mortality of 50-75% and 100 % mortality in recipient twin [6]. ...
... Twin studies provide compelling evidence for both the inherited influence on body weight (14)(15)(16) and the critical role of environmental factors in promoting obesity in people with a propensity to gain weight (17)(18)(19). Because the genetic similarities of twins are easily understood, twins are useful for elucidating the contribution of inherited factors to illness and health (20,21). Monozygotic twins are genetically identical, of the same sex, and exactly matched for age. ...
Background:
Neural responses to highly energetic food cues are robust and are suppressed by eating. It is not known if neural responsiveness to food cues is an inherited trait and possibly even one that mediates the genetic influences on body weight that have been previously observed.
Objective:
We investigated the inherited influence on brain responses to high-calorie visual food cues before and after a meal.
Design:
With the use of a monozygotic twin study design, 21 healthy monozygotic twin pairs consumed a standardized breakfast and, 3.5 h later, underwent the first of 2 functional MRI (fMRI) scans with the use of visual food cues. After the first fMRI session, twins consumed a standardized meal, which was followed by the second fMRI. Serial ratings of appetite and food appeal were obtained. An ad libitum buffet was used to measure total caloric and macronutrient intakes. Intraclass correlations (ICCs) were used to test for inherited influences by comparing whether intrapair similarity was greater than interpair similarity.
Results:
Body mass index was highly correlated within twin pairs (ICC: 0.96; P < 0.0001). ICCs also showed a strong intrapair similarity for the meal-induced change in hunger (ICC: 0.41; P = 0.03), fullness (ICC: 0.39; P = 0.04), and the appeal of fattening food (ICC: 0.57; P < 0.001). Twins ate a similar number of kilocalories at the buffet (ICC: 0.43; P = 0.02). Before the meal, the global brain activation across regions involved in satiety processing was not more similar in twins than in unrelated individuals. However, significant ICCs were present after the meal (ICC: 0.39; P = 0.04) and for the meal-induced change in activation by high-calorie visual food cues (ICC: 0.52; P < 0.01).
Conclusion:
Inherited factors influence both satiety perception and the effect of a meal to alter regional brain responses to images of highly energetic food. This trial was registered at clinicaltrials.gov as NCT02483663.
... Multiple pregnancy account for 1.5% of all pregnancies, with approximate perinatal morbidity of 10% (Hrubec and Robinette, 1984). Acardiac twining also referred to as the twin reversed arterial perfusion sequence (TRAP) represents an extreme manifestation of the twin transfusion syndrome and has an incidence of 1 in 35 000 deliveries (Chanthasenanant and Pongrojpaw, 2005) amounting to an average risk of 1% among monozygotic twins. ...
... Multiple pregnancy account for 1.5% of all pregnancies, with approximate perinatal morbidity of 10% (Hrubec and Robinette, 1984). Acardiac twining also referred to as the twin reversed arterial perfusion sequence (TRAP) represents an extreme manifestation of the twin transfusion syndrome and has an incidence of 1 in 35 000 deliveries (Chanthasenanant and Pongrojpaw, 2005) amounting to an average risk of 1% among monozygotic twins. ...
... With crucial aspects such as age, sex, and many environmental factors controlled for, monozygotic twins are an excellent system for studying discordant phenotypes, for example, in DNA methylation profiles. Early monozygotic twin studies were primarily motivated by identification and research on similar traits, also known as concordant studies [134]. More recently, the focus has shifted to uncovering the mechanisms behind discordant, or variable, phenotypes among monozygotic twins, particularly in prominent diseases. ...
Methylation at the 5 position of cytosine is a form of covalent DNA modification found in a variety of species including plants and mammals. It plays an important role in gene regulation, chromatin structure, and a variety of other biological processes. It serves as an epigenetic mark and has been shown to change in response to environmental factors and disease. Owing to its importance in gene regulation, there has been considerable interest in trying to understand the role of DNA methylation in the production of organism-level phenotypes and especially in its contribution to human health and disease. Studies in many organisms have revealed large amounts of variation in DNA methylation between individuals. This interindividual variation in DNA methylation is highly complex. The amount of variation detected is locus- and tissue-specific and can be caused by genetic as well as environmental factors. In this chapter, we review the available data on interindividual variation in DNA methylation, its origins, and its consequences with a particular focus on its role in human disease.
... Twin studies are valuable tools to study the genetic and environmental contribution in the etiology of complex disorders. 176 Hereby, the frequency of disease occurring in both members of the twin pair is calculated (concordance) whereafter the concordance rates of identical and dizygotic twins are compared. 177 High concordance rates in monozygotic twins and much lower concordance rates in dizygotic twins imply a strong genetic influence. ...
Caroline Eykens,1,2 Wim Robberecht1–31Research Group Experimental Neurology, Department of Neurosciences, KU Leuven – University of Leuven, Leuven, Belgium; 2Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium; 3Department of Neurology, University Hospitals Leuven, Leuven, BelgiumAbstract: Deciphering the genetic architecture of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disorder of the motor neuron system, is important to understand the etiology of this fatal disease as well as to develop customized ALS therapies based on the patient's genetic fingerprint. In this review, we discuss the genetic basis of ALS, and attempt to link the causal genes to three highly interrelated pathogenic mechanisms: dysproteostasis, RNA dysregulation, and axon dysfunction. In addition, we address the clinical and biological implications of these genetic findings. Furthermore, we explore to what extent genetic knowledge can be converted into targeted and personalized treatments.Keywords: amyotrophic lateral sclerosis, frontotemporal dementia, genetics, disease modifiers, personalized medicine
... Genes that affect these neurotransmitter systems could contribute to the expression of both depression and LBP. However, the environmental influences on the relationship between depression and LBP should not be disregarded, as it is possible that the genetic identity of MZ twins predisposes them to select a more similar environment than DZ twins, 16 in which case the difference in results between MZ and DZ case-control analyses could not be attributable solely to genetic differences. ...
Although the co-occurrence of low back pain (LBP) and depression is common, the nature of this association remains unclear. We aimed to investigate whether symptoms of depression are associated with LBP after adjusting for various confounders, including genetics. We used cross-sectional data from 2148 twins from the Murcia Twin Registry, Spain. All twins answered questions about lifetime prevalence of LBP (outcome variable) and symptoms of depression, collected through two instruments, deriving 3 measures: (1) self-report feelings of depression and anxiety; (2) state depression, and (3) trait depression. First, associations were investigated using logistic regression analysis of the total sample. We performed subsequent matched within-pair twin case-control analyses with all complete twin pairs discordant for LBP regardless of zygosity, and separately for dizygotic and monozygotic pairs. This sequential analysis allows for more precise estimates of the relationship between variables, as in each step, the impact of early shared environment and genetics is further considered. Symptoms of depression and anxiety were associated with higher prevalence of LBP in the total sample analysis (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.31-2.05), and this relationship was stronger in the subsequent case-control analysis (OR, 1.74; 95% CI, 1.13-2.69) and dizygotic case-control analysis (OR, 2.39; 95% CI, 1.39-4.08) but disappeared when the analysis was conducted for monozygotic twins (OR, 0.92; 95% CI, 0.42-2.05). A similar pattern was found for state and trait depression. The depression-LBP relationship disappears when high levels of control for confounding factors are applied and seems to be driven by genetic or environmental factors that influence both conditions.
Studying sex or gender differences for any human trait or condition by comparing males and females from opposite-sex twin pairs is a powerful way to protect from bias arising from uncontrolled familial factors (both genetic and nongenetic) while controlling for age and year of birth. In this chapter, we briefly introduce this study design for medical research and provide examples of its application in studies of physical and mental health. We also explore evidence suggesting that sharing the mother’s womb with an opposite-sex cotwin might produce sex differences for certain health outcomes—with implications for the interpretation of opposite-sex twin studies. Finally, we argue that the investigation of sex or gender differences of opposite-sex twin pairs offers the opportunity for more precise insights into the role of such differences in determining health and disease, both at the individual and population level.
Historically monozygotic (MZ) twins have been considered to be genetically identical; a notion that has been challenged, in part due to the increasing number of phenotypically and/or genotypically discordant twins proven to be MZ. This realization has led to many advances in genetic research, including, but not limited to, a better understanding of certain disease pathomechanisms, insight regarding the phenotypic variability and severity spectrum of genetic disorders, the identification of novel mutations and disease-causing genes, and unraveling the complex interplay between genetic, epigenetic and environmental factors on human health. In this chapter, we will briefly discuss the genetic background of chromosomal anomalies and monogenic disorders, then we will present the main mechanisms by which twin discordance may emerge, and finally, we will present aspects of the multistep and multifactorial causal mechanism of childhood acute leukaemia discovered through MZ twin studies.
p>The aim of this study was to explore two main hypotheses. Firstly, that the greater similarity in glucose tolerance and blood pressure in monozygotic twins compared with dizygotic twins is due to their more similar prenatal environment. Secondly, that within pair differences in glucose tolerance and blood pressure would be determined by differences in size at birth.
A longitudinal study of births in the city of Birmingham from 1950 onwards provided the sampling frame for the study and allowed a population-based sample of twins to be studied. Twins born between 1950 and 1954 were identified and followed up. They were visited at home where their blood pressure was measured. They were then invited to attend a clinic for an oral glucose tolerance test.
Adult levels of glucose tolerance and blood pressure were more highly correlated in the monozygotic than dizygotic twins. These trends were not explained by size at birth. Examination of within pair differences in glucose tolerance revealed significant associations between size at birth and insulin resistance in the monozygotic twins. However, inconsistencies in these trends and the fact that they were based on small numbers of twin pairs weakened these findings. Furthermore, the well documented inverse associations between birth size and adult glucose tolerance and blood pressure in singleton populations were absent in the twins.
The findings of this study were not consistent with the fetal origins hypothesis. The association of within pair differences in birth size and insulin resistance in monozygotic twins does, however, suggest an effect of birth size that is independent of genetic factors.</p
The imbalance between pathogenic and beneficial species of the intestinal microbiome and metabolism in rheumatoid arthritis (RA) remains unclarified. Here, using shotgun-based metagenome sequencing for a treatment-naïve patient cohort and a “quasi-paired cohort” method, we observed a deficiency of butyrate-producing species and an overwhelming number of butyrate consumers in RA patients. These outcomes mainly occurred in patients with positive ACPA, with a mean AUC of 0.94. This panel was also validated in established RA with an AUC of 0.986 in those with joint deformity. In addition, we showed that butyrate promoted T regs , while suppressing T convs and osteoclasts, due to potentiation of the reduction in HDAC expression and down-regulation of proinflammatory cytokine genes. Dietary butyrate supplementation conferred anti-inflammatory benefits in a mouse model by rebalancing T FH cells and T regs , as well as reducing antibody production. These findings reveal the critical role of butyrate-metabolizing species and suggest the potential of butyrate-based therapies for RA patients.
Using a novel methodology termed the death discordant twin method, it has been possible to carry out an epidemiological study into the possible causes of sporadic MND. The study population was the largest twin sample so far collected worldwide for this rare disease, and identified 75 twin pairs—24 monozygotic and 51 dizygotic. This involved a comprehensive and detailed search of the MND death certificate population for England and Wales between 1979–1989 inclusive. The twin sample was utilised for two different purposes: 1) The estimation of the genetic contribution to sporadic MND; and 2) the formation of matched pairs for a case-control study of environmental factors. An extensive review of germane hypotheses and research was made and is reported with reference to relevant papers. Following a critique of the methods and problems of many traditional twin studies, the advantages of this new method are discussed. The study results are analysed and detailed together with statistical evaluation, and the genetic contribution estimated. Four monozygotic probands from two concordant pairs were identified, producing a MZ proband concordance rate of 17.4%. This was reduced to 10% when two probands were determined to have had familial MND. No dizygotic concordant pairs were found, but a "coefficient of genetic determination" ('G') between 0.38–0.85 was derived, using the methods of Falconer 1965 and Smith 1974. This supports a multifactorial aetiology for MND, probably involving several genetic factors, i.e. a single gene defect is excluded. The environmental risk factors were assessed using Odds Ratios (OR) with 95% Confidence Intervals (Cl). The statistically significant factors which held true during conditional logistic regression modelling were 'regular vehicle maintenance' [OR = 7.0 (CI 1.3–89.9)], and 'occupational paint usage' [OR = 3.75 (CI 1.1–17.1)]. Other factors were of clinical interest. Many of the environmental factors identified in previous studies to be associated with increased risk for MND were not verified.
We consider a two-sample problem where data come from symmetric distributions. Usual two-sample data with only magnitudes recorded, arising from case-control studies or logistic discriminant analyses, may constitute a symmetric two-sample problem. We propose a semiparametric model such that, in addition to symmetry, the log ratio of two unknown density functions is modeled in a known parametric form. The new semiparametric model, tailor-made for symmetric two-sample data, can also be viewed as a biased sampling model subject to symmetric constraint. A maximum empirical likelihood estimation approach is adopted to estimate the unknown model parameters, and the corresponding profile empirical likelihood ratio test is utilized to perform hypothesis testing regarding the two population distributions. Symmetry, however, comes with irregularity. It is shown that, under the null hypothesis of equal symmetric distributions, the maximum empirical likelihood estimator has degenerate Fisher information, and the test statistic has a mixture of χ2 -type asymptotic distribution. Extensive simulation studies have been conducted to demonstrate promising statistical powers under correct and mis-specified models. We apply the proposed methods to two real examples.
Background:
Musculoskeletal conditions are highly prevalent in our ageing society and are therefore incurring substantial increases in population levels of years lived with disability (YLD). An evidence-based approach to the prognosis, prevention, and treatment of those disorders can allow an overall improvement in the quality of life of patients, while also softening the burden on national health care systems.
Methods:
In this Masterclass article, we provide an overview of the most relevant twin study designs, their advantages, limitations and major contributions to the investigation of traits related to the domain of musculoskeletal physical therapy.
Conclusions:
Twin studies can be an important scientific tool to address issues related to musculoskeletal conditions. They allow researchers to understand how genes and environment combine to influence human health and disease. Twin registries and international collaboration through existing networks can provide resources for achieving large sample sizes and access to expertise in study design and analysis of twin data.
Autoimmunity and chronic inflammation recognize numerous shared factors and, as a result, the resulting diseases frequently coexist in the same patients or respond to the same treatments. Among the convenient truths of autoimmune and chronic inflammatory diseases, there is now agreement that these are complex conditions in which the individual genetic predisposition provides a rate of heritability. The concordance rates in monozygotic and dizygotic twins allows to estimate the weight of the environment in determining disease susceptibility, despite recent data supporting that only a minority of immune markers depend on hereditary factors. Concordance rates in monozygotic and dizygotic twins should be evaluated over an observation period to minimize the risk of false negatives and this is well represented by type I diabetes mellitus. Further, concordance rates in monozygotic twins should be compared to those in dizygotic twins, which share 50% of their genes, as in regular siblings, but also young-age environmental factors. Twin studies have been extensively performed in several autoimmune conditions and cumulatively suggest that some diseases, i.e. celiac disease and psoriasis, are highly genetically determined, while rheumatoid arthritis or systemic sclerosis have a limited role for genetics. These observations are necessary to interpret data gathered by genome-wide association studies of polymorphisms and DNA methylation in MZ twins. New high-throughput technological platforms are awaited to provide new insights into the mechanisms of disease discordance in twins beyond strong associations such as those with HLA alleles.
A Vietnam Era (1964-1975) Twin Registry of American male-male veterans born between 1939 and 1955 has been developed to provide a study sample for research evaluating the impact of Vietnam service on the medical and psychosocial aspects of health. In preparation for developing the Registry, several alternative sources of twins and methods for identifying twins were investigated. A computerized database of veterans discharged from the military after 1967 was selected as the source because it contains about 50% of the total Vietnam era veteran population, is reasonably unbiased, and provides a feasible method for identifying twins. Twins were identified using an algorithm which involved matching entries on the database for same last name, different first name, same date of birth, and similar social security number. Twin status was confirmed by review of military records. The registry, now complete, is composed of 7,400 twin pairs. It will be an important resource for future research projects.
Escalating health care costs, driven by the use of high technology to manage rather than cure chronic degenerative diseases in rapidly aging populations, are seriously straining Western economies. What are needed are strategies which seek to mitigate those high order events that ultimately cause disease. Prevention involves deliberately changing not only environments and lifestyles, but also the nature of health care and perhaps even human biology itself. It is argued that a similar shift has occurred in disaster planning, where emphasis has moved from rescuing survivors to achieving greater safety through better planning and more sophisticated infrastructural design. That is, disaster specialists try to avoid rather than respond to catastrophes. A similar approach is long overdue in health care.
Several animal models are now available for the study of pregnancy complicated by diabetes mellitus and thus studies of islet transplantation in these pregnant animals can also be performed. Animals may be made hyperglycemic by the use of alloxan or streptozotocin. Infusion protocols of glucose and/or insulin have been described in several species including rats and monkeys. Recently described genetic models include the BB Wistar rat, the NOD mouse, the C57/KsJdb+/+m mouse, and the Chinese hamster with spontaneous diabetes (CHAD). The NOD mouse is particularly attractive for studies of transplantation since it has several features in common to the human autoimmune counterpart. Studies of subcutaneous fetal islet transplantation in this model as well as in humans during gestation suggest improved graft survival and insulin secretory capacity. The nature of the factors during pregnancy that lead to enhanced tissue vascularization, improved tissue growth and secretory capacity, and decreased immunological response in pregnant recipients are noteworthy and warrant further study.
Infants of multiple gestations are subject to all the diseases and disorders that singletons are, but with two additional levels of consideration—the degree of concordance of the abnormality, and the significance of the twinship to the pathophysiology or prevalence. The caveats surrounding twin studies and the interpretation of the significance of concordance of an observation in twins have been discussed in Chapter 1. However, it is worth restating the importance of careful pathologic documentation of placental findings and autopsy studies to the validity of any study of patterns of disease in twins.
The mystery of childbirth has been associated with beliefs and practices arising from humankind’s imagination and ingenuity, and these have been yielding only gradually to increasing knowledge of the physiology of reproduction as such information has been more widely understood. When pregnancy resulted in the birth of more than one child at a time, the mystery was compounded and the fascination with multiple births persists.2–4 Fortunately for the infants and mother, this interest is now largely benevolent social and scientific curiosity, although for some people there is still the uneasy sense that twins, particularly “identical” twins, have an added dimension to life that ordinary singletons are denied and cannot understand. This “specialness” of twins is exemplified in the twin cult of the Yoruba in Africa, who have had the highest twinning rate in the world.5
Our concepts of the possible mechanisms of twinning, the rates of these different mechanisms, and the factors that influence those rates have developed considerably in recent years with the aid of technical advances in two disciplines—prenatal diagnosis and DNA analysis. The increasing use of ultrasound examination in early pregnancy has identified far more pregnancies that begin with a multiple gestation than pregnancies that actually end with multiple infants delivered (see Chapter 5). Studies to date suggest that much of this early loss is of one particular type of twins, so our concepts of the rates of the different mechanisms of twinning may need to be revised. Also, it used to be that twins either looked alike (identical) or not (fraternal) and that was all that could be said. Now, it is possible to determine which parent provided a specific portion of the genome in each twin, and subtle and unusual varieties of biologic mechanisms of twinning that were only theoretical constructs before can be refuted or confirmed (see below). Finally, the influences governing twinning are increasing as the modes of twinning multiply.
Mendel’s fundamental discoveries are usually summarized in three laws:1.
Crosses between organisms homozygous for two different alleles at one gene locus lead to genetically identical offspring (F1 generation), heterozygous for this allele. It of no importance which of the two homozygotes is male and which is female (law of uniformity and reciprocity). Such reciprocity applies only for genes not located on sex chromosomes.
2.
When these F1 heterozygotes are crossed with each other (intercross), different genotypes segregate out: One-half is heterozygous again and one-quarter is homozygous for each of the parental types. This segregation 1:2:1 is repeated after crossing of heterozygotes in the following generations, whereas the two types of homozygotes breed pure. As noted above (Sect. 1.4), Mendel interpreted this result correctly, assuming formation of two types of germ cells with a 1:1 ratio in heterozygotes (law of segregation and law of purity of gametes).
3.
When organisms differing in more than one gene pair are crossed, every single gene pair segregates independently and the resulting segregation ratios follow the statistical law of independent segregation (law of free combination of genes).
Familial risk in dementia of Alzheimer type (DAT) can be investigated by either or both genetic and epidemiological studies. The main objective of these latter studies is to examine whether an increased familial risk does exist. Case-control studies have yet to provide clear evidence for familial aggregation of DAT. The inconclusiveness of these results is due to the very small number of studies with positive results and to methodological problems which are present in studies of both positive and negative outcome. Both positive and negative findings must be carefully discussed and bias, such as the difference in age distributions of relatives or recall bias in information obtained from respondents, must be considered for either type of result. Negative findings must be interpreted in the context of data quality and sample size. The compatibility of positive findings with epidemiological characteristics of DAT in the general population must be verified.
Im Gegensatz zur Vererbung durch ein Gen, entweder autosomal oder geschlechtsgebunden, erlauben Vererbungsmuster nicht die Diagnose einer multifaktoriellen Vererbung. Durch ein Gen determinierte Merkmale treten diskontinuierlich auf mit mutierten Allelen, die einen bestimmten Phänotyp erzeugen. Multifaktorielle Merkmale können kontinuierlich oder diskontinuierlich auftreten, stets ist das Merkmal jedoch durch das Zusammenspiel mehrerer Gene an verschiedenen Lozi determiniert. Jedes Gen trägt durch einen kleinen, additiven Effekt zusammen mit Umweltfaktoren zur Ausprägung des Merkmals bei. Für diskontinuierliche, multifaktorielle Merkmale, wie etwa die Spina bifida, besteht bei den betroffenen Familien ein höheres Risiko als bei der Allgemeinbevölkerung. Im Vergleich zu dem von Familien mit einem durch ein Gen determinierten Erbleiden ist das Risiko jedoch gering und fällt für entferntere Verwandte schnell auf das Durchschnittsrisiko. So ist in der Praxis der Träger eines diskontinuierlichen multifaktoriellen Merkmals oft der einzige Betroffene in seiner Familie.
In a remarkable paper that correlates prenatal events and discordance of twins with postnatal outcome, Price (1950) emphasized the importance of “prenatal biases.” He was much concerned with the influence of placentation upon twin development, an aspect that had not often been considered in twin studies. Similar ideas have more recently been echoed by Phillips (1993) who emphasized the influence of the proximity of twin placentas on their ability to support fetal growth. But it was Galton (1875), cousin of Charles Darwin, and after whom the Galton Institute of Genetics in London is named, who was probably the first to suggest that twins, if properly studied, would yield information that might allow us to discriminate between the effects of heredity and those of the environment. It was his famous “Nature vs. Nurture” concept. The extensive studies conducted by Friedrich Schatz at about the same time, suggested that prenatal influences among twins found reflection in the ultimate outcome of the twins. He was instrumental in clarifying that placental study is essential for this understanding. His extensive work is annotated in a bibliographic oddity (Schatz 1900). It summarized all of his papers and citations therein. Some of his numerous contributions were partially translated for the book on twin placentation by Strong and Corney (1967). A concise review of the biologic aspects of the human twinning process was published by Benirschke and Kim (1973), and the new volume on “Twinning and Twins” by MacGillivray and his colleagues (1988) summarizes most relevant aspects of this interesting phenomenon of nature. Baldwin (1994) has produced a remarkable volume that contains all relevant aspects of placentation of multiple pregnancies, and it is well illustrated. Finally, Gall (1996) has summarized all practical aspects of multiple gestations, especially the clinical manifestations and therapy. Several cases of hydatidiform mole in twin gestations have been reported (e.g., Chu et al. 2004). These are discussed in more detail in the Chap. 22.
The number of multifetal gestations has increased significantly since 1980, accounting for 1.5% of all pregnancies in the United States (Sepulveda 1997). This is mainly related to treatment of infertility and to an aging maternal population (Divon and Weiner 1995, Edwards et al. 1995).
Twin-twin transfusion syndrom (TTTS) is a serious complication of monochorionic twin pregnancies. It is the result of an unbalanced transfusion of blood across placental vascular anastomoses. TTTS appears predominantly in the second trimester of pregnancy characterized by discordance of growth as well as polyhydramnios in the recipient and oligo-/anhydramnios in the donor. Prenatal diagnosis is possible by non-invasive and invasive methods. The prognosis of the untreated TTTS is very poor. Serial amniocenteses and laser therapy are used resulting in survival rates of about 60%. Intrauterine death of one twin is associated with a high risk of morbidity in the surviving twin. Monochorionic twins have to be identified in early pregnancy. Close surveillance is necessary to diagnose TTTS at an early stage of the disease.
A number of twin studies of epilepsy, both larger series and individual case studies, have been reported. These have shown clearly that both genetic and environmental factors are involved, but they have not contributed significantly to the understanding of basic mechanisms. Meanwhile, there has been rapid progress in the neurosciences, with respect to brain structure and function, brain imaging, neurophysiology, and biochemistry at the cellular and molecular levels [8, 27]. New questions have arisen and new methods for study have been developed.
Cerebral infarction in young adults Stroke in neonates and children Diagnostic strategies in children, neonates, and young adults with stroke Atherosclerotic cerebral infarction in young adults Non-atherosclerotic vasculopathies Cardiac disorders and stroke in children and young adults Cerebral infarction and migraine Hemostatic disorders presenting as cerebral infarction Stroke and pregnancy Rare genetic disorders predisposing to cerebral infarction Cerebral venous thrombosis in children and young adults Neonatal intercranial hemorrhage Spontaneous intracerebral hemorrhage in children and young adults Spontaneous subarachnoid hemorrhage in children and young adults.
A prospective twin study on age-related macular degeneration (AMD) recruited 83 monozygotic pairs, 28 dizygotic pairs, and one triplet set from 1986 through 1993. Zygosity was determined by genetic testing of red cell markers, HLA antigens, or specific DNA loci. There were no twin pairs in which I collected data on only one twin. To decrease ascertainment bias, after 1991 the recruitment notice did not mention AMD, and I did not ask about a history of eye disease before the eye examination. Because of this, twin pairs recruited from 1986 through 1991 were statistically analyzed separately from those after January 1, 1992. From 1986 through 1991, 23 twin pairs were recruited; 11 monozygotic and 2 dizygotic pairs had nonAMD retinal changes or no retinal abnormalities, 9 monozygotic pairs with AMD were all concordant, and 1 dizygotic pair was discordant for basal laminar drusen. The concordance rate of AMD did not differ significantly between monozygotic and dizygotic twin pairs (P = .10) for 1986 through 1991. In 1992 and 1993, 88 twin pairs and one triplet set were recruited; 49 monozygotic and 19 dizygotic pairs had nonAMD retinal changes or no retinal abnormalities, 14 monozygotic pairs with AMD were all concordant, and 2 of 7 dizygotic pairs were concordant for AMD. The nonidentical triplets (1 with and 2 without AMD) were categorized as one of the discordant dizygotic pairs in the statistical evaluation. In nontwin age-matched (within 2 or 5 years of age) or age- and sex-matched sibling pairs the concordance rate of AMD ranged from 16% to 25%. The concordance rate of AMD was significantly higher in monozygotic than in dizygotic twins (P = .001) for 1992 and 1993. The concordance rate was higher for monozygotic twin pairs recruited in 1992 and 1993 than in any of the four subsets of nontwin age-method or age- and sex-matched sibling pairs (P < .0001). Overall, from 1986 through 1993, 23 of 23 monozygotic and 2 of 8 dizygotic twin pairs were concordant for AMD; this included the one dizygotic pair which was discordant for basal laminar drusen. The data of this study strongly suggest a genetic predisposition to AMD.
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
Die pathologisch-anatomische Untersuchung der Plazenta und ihrer Anhänge sollte heute bei Abort und Totgeburt, bei jedem erkrankten Neugeborenen und bei jeder Risikoschwangerschaft und -geburt zum diagnostischen Standard gehören. Ihre Aussagemöglichkeiten hinsichtlich Ursache, Pathogenese und Prognose bei Kind, Mutter und nachfolgenden Schwangerschaften werden zu wenig genutzt. Das Kapitel ist dreigeteilt. Die Pathologie der Plazenta, der Nabelschnur und der Eihaut beinhaltet Untersuchungsgang und -ziele, beschreibt systematisch die makroskopischen und mikroskopischen Veränderungen und deren klinische Bedeutung. Die Pathologie der fetoplazentaren Einheit umfasst die Veränderungen in der Plazenta und im Fetus/Neugeborenen bei intrauterinen und konnatalen Infektionen, bei fetalen und mütterlichen Erkrankungen sowie bei Drogenabusus. Der letzte Teil befasst sich mit der Mehrlingsschwangerschaft, speziell mit Plazentation und Morphologie der Zwillingsplazenta und dem fetofetalen Transfusionssyndrom.
OBJECTIVES: Chronically fatiguing illness, defined as fatigue for at least 6 months, has been associated with various physical health conditions. Our objective was to determine whether there is a significant relationship between chronically fatiguing illness and 10 clinical conditions that frequently appear to be associated with fatigue, adjusting for the potentially confounding effects of psychiatric illness.
DESIGN: A co-twin control study controlling for genetic and many environmental factors by comparing chronically fatigued twins with their nonfatigued co-twins.
SETTING: A nationally distributed volunteer twin registry.
PARTICIPANTS: The study included 127 twin pairs in which one member of the pair experienced fatigue of at least 6 months’ duration and the co-twin was healthy and denied chronic fatigue. Fatigued twins were classified into three levels using increasingly stringent diagnostic criteria.
MEASUREMENTS AND MAIN RESULTS: Twins reported on a history of fibromyalgia, irritable bowel syndrome, multiple chemical sensitivities, temporomandibular disorder, interstitial cystitis, postconcussion syndrome, tension headache, chronic low back pain, chronic pelvic pain (women), and chronic nonbacterial prostatitis (men). The prevalence of these comorbid clinical conditions was significantly higher in the fatigued twins compared to their nonfatigued co-twins. Most notably, compared to their nonfatigued co-twins, the chronically fatigued twins had higher rates of fibromyalgia (> 70% vs <10%) and irritable bowel syndrome (>50% vs <5%). The strongest associations were observed between chronic fatigue and fibromyalgia (odds ratios >20), irritable bowel syndrome, chronic pelvic pain, multiple chemical sensitivities, and temporomandibular disorder (all with odds ratios ≥4). Regression analysis suggested that the number of comorbid clinical conditions associated with chronic fatigue could not be attributed solely to psychiatric illness.
CONCLUSIONS: Chronically fatiguing illnesses were associated with high rates of many other clinical conditions. Thus, patients with chronic fatigue may present a complex clinical picture that poses diagnostic and management challenges. Nonetheless, clinicians should assess such patients for the presence of comorbid clinical conditions. Future research should provide a better understanding of the temporal relationship of the onset of fatigue and these conditions, and develop strategies for early intervention.
Genealogical records containing birth and death dates for completed families have been analyzed to compare the longevity of twins, sibs and parents. The data are restricted to twins and sibs who survived to adulthood and married. The findings, similar to those found with respect to fertility (Wyshak and White, 1969), show that twins, especially male twins, are disadvantaged in comparison with their male sibs. Sib‐sib and parent‐offspring correlation analysis confirmed that there is a genetic component in the determination of life span, but environmental factors contribute more to the total variation. No evidence of a stronger maternal than paternal effect was found. Twin bearers also lived longer than nontwin bearers. Even among persons who survived to age SO or more, parents of twins had more children and lived slightly longer than their twin and nontwin offspring. Regression analysis for persons who survived to SO or longer indicated that, in addition to life span of parents, secularity (year of death) and fertility (number of children borne) were the best predictors of longevity, though only a small proportion of the variation could be accounted for by these and other demographic variables. Life span has shown a consistent increase over time from the seventeenth century through the nineteenth century, while fertility has tended to decline. However, among persons surviving to age SO, when the relation between secularity and fertility and secularity and longevity is controlled, a significant correlation between fertility and longevity remains. This relation, observed in populations that did not practice voluntary family size limitation, would not be found in contemporary data. Maternal mortality accounted for the shorter life span of women than for men; eliminating its effect gives women a slight advantage. The fertility and longevity experience of migrants who survived to age SO is more favorable than that of persons who did not migrate.
The role of variance analysis in human genetics is discussed.
The general model and assumptions required to estimate genetic variance from monozygotic (MZ) and dizygotic (DZ) twins are reviewed. Using the among and within twin pair mean squares, two independent estimates of genetic variance are obtained: G(WT) = within DZ mean square, within MZ mean square and G(AT) = among MZ mean square, among DZ mean square. This model holds only if the total mean squares of DZ and MZ twins differ only by chance fluctuation. For most cases, G(WT) is presented as an adequate measure of genetic variance, but it may be refined by adjustment by a weighted mean with G(AT). The weighted mean proposed was a minimum variance estimate in which G(AT) and G(WT) were combined according to the reciprocal of their variances. If the total mean squares differ more than could be expected by chance, then environmental factors were postulated as being unequal for MZ and DZ twins and the arithmetic mean of G(WT) and G(AT) must be used as un unbiased estimate of twin genetic variance.
A study of cardiovascular risk factors in middle-aged twin men provided an opportunity to test for genetic variability in the SMA 12/60 (Technicon) battery of clinical chemistry tests. Classical twin methodology was used to analyze the variation of monozygotic and dizygotic twins. In addition, frequency of co-twin contact was used to control for ef¬fects of differences in shared environment. Genetic vari¬ability played a definite role in controlling four of the 11 reported tests: one-hour serum glucose, serum urea ni¬trogen, uric acid, and bilirubin. No genetic variation was found for lactate dehydrogenase, phosphorus, and alkaline phosphatase. Significantly higher means for calcium, total protein, albumin, and aspartate aminotransferase in monozygotic twins precluded any statement about heredity and environment for these tests.
A method of estimating the probability of dizygotic and monozygotic twin pairs is described. Parent-child and sib-sib frequency tables for the ABO, MNS and Rhesus blood-group systems and formulae for obtaining these tables for the P, Lutheran, Kell, Duffy, Kidd and non-secretor (or Lewis) systems are given.
Tables of the distribution of differences in total finger ridge count and atd palmar angles are also given.
The probability that a given twin pair is monozygotic is estimated in two worked examples.
Results from heritability of liability model of Falconer (1965) have been revised, eliminating two sources of bias. The results have been graphed for convenient usage, and in the absence of environmental similarities among relatives can apply to all kind of relatives. Confidence levels for the heritability (or correlation) estimates can also be read directly off the graph.
The results also apply to concordance rates in MZ twins. They show that, in the absence of environmental similarities, concordance rates for a disease in MZ twins will only be high if the heritability is very high. Thus a low concordance rate in MZ twins cannot be taken to prove that genetic factors are not important in the predisposition to a disease.
A mailed questionnaire dealing with similarity in childhood, and how often and by whom the twins were mixed up, was applied to 290 same-sex adult twin pairs. For about 75% of pairs ten genetic markers were analysed. The agreement in zygosity classification between questionnaire and blood typing was high. Irrespective of whether raw scores of discriminant function analysis was applied, the agreement was nearly 95%. When a decision tree was applied, the percentage rose to nearly 96%. Considering that probably four of the twin pairs were wrongly classified as MZ by genetic markers, the percentage rose to 96 and 98, respectively.
The formulas needed in the determination of monozygosity in twin pairs using genetic markers are derived and presented. A general formula for the calculation of concordance probabilities independent of gene frequencies and allele number is derived, enabling either manual computation or computer programming for any Mendelian markers usable in twin zygosity diagnosis.
Three different dosages of vitamin C, dependent on body weight, were administered to 44 school-aged monozygotic twins for five months using a double-blind, co-twin control study design. The mothers recorded daily observations of cold symptoms, and multiple biochemical, anthropometric, and psychological measurements were made at the beginning and end of the study. Paired comparisons showed no significant overall treatment effect on cold symptoms, but the response was not uniform in all sub-groups. Treated girls in the youngest two groups had significantly shorter and less severe illness episodes, and an effect on severity was also observed in the youngest group of boys. The seven treated twins in the latter group also grew an average of 1.3 cm more than their untreated co-twins during the five-minth period of the study.
Data from individual interviews, blood grouping analyses, and ratings of photographs of a large sample of adolescent twins were examined in order to assess the accuracy of zygosity determination by alternate methods. Although the accuracy of the twins themselves and of the raters was above chance, it was not sufficiently high to justify diagnosis by these methods rather than by blood grouping analyses.
Feinleib, M. (National Heart, Lung, and Blood institute, NIH, Federal Bldg., Room 2C08, Bethesda, MD 20014), R. J. Garrison, R. Fabsitz, J. C. Christian, Z. Hrubec, N. O. Borhani, W. B. Kannel, R. Rosenman, J. T. Schwartz and J. O. Wagner. The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol 106:284–295, 1977.
Coronary heart disease (CHD) risk factors were studied in 250 monozygotic (MZ) and 264 dizygotic (DZ) male veteran twin pairs, aged 42–56. All coronary heart disease risk factors studied showed significant correlations in both MZ and DZ twins. Substantial genetic variation was detected for height, blood pressure, glucose intolerance, uric acid, plasma triglyceride, and relative weight but little or no significant genetic variability in low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), total plasma cholesterol or hematocrit was demonstrable. These findings suggest that familial aggregation results from genetic influence on blood pressure, glucose intolerance, uric acid, triglyceride and, possibly, obesity, while largely shared environmental factors contribute to familial similarities in HDL, LDL, total cholesterol and hematocrit.
The data presented here indicate that different influences affect dermatoglyphic pattern development in MC-MZ and DC-MZ twins. Only five of 84 variables had significant mean differences but their clustering suggested a real difference in mean placement of the atd angle. Nineteen of 84 variables had significantly different within-pair mean squares for the two twin types. Larger numbers of twins will be required to obtain accurate estimates of the magnitude of the dermatoglyphic differences between MC-MZ and DC-MZ twins. Studies of dermatoglyphics in MC-MZ and DC-MZ twins are important to the understanding of factors which influence early embryonic development and when better documented may provide a mechanism for retrospectively diagnosing placental type of MZ twins.
Mean twin, triplet, and quadruplet birth rates in Japan from 1951 to 1968 were 6.41, 0.056, and 0.00094 per 1,000, respectively. In 1974 the corresponding figures were 5.83, 0.059, and 0.00329. No quintuplets were born in the former period, but a set was born in the latter year, the rate being 0.47 per million. From 1955 to 1966 the MZ twinning rate increased slightly, but decreased thereafter. This increase was limited to live-born MZ twins, particularly in the higher maternal age groups. The DZ twinning rate declined in the entire period, particularly in higher maternal age groups. This decline appeared to be essentially limited to fetal deaths. Among live births the MZ twinning rate underwent a nearly linear increase with maternal age, whereas the DZ twinning rate attained a mode in the maternal age group 35--39 years. The MZ and the DZ twinning rates among fetal deaths by maternal age had unimodal distributions with modes in maternal age groups 25--29 and 30--34 years, respectively. As to the DZ twinning rate, a geographical cline was noted, with a high rate in the northeast of Japan; the rate was positively correlated with latitude, which also positively correlated with the presence of multiple births among relatives. A negative but nonsignificant correlation was seen between the DZ twinning rate and the proportion of mothers treated with ovulation-inducing hormone. The proportion was higher in mothers of unlike-sexed twins than in those of like-sexed twins and in mothers of triplets than in those of twins. An association between DZ twinning rate and age-specific fertility per married woman is suggested to exist among higher maternal age groups in the northeast part of Japan in earlier years.
Estimation of the twin concordance rate for a disease often requires two stages. First, the disease is ascertained in a population or in a population sample, and such twins as are found with the disease become probands. Second, twin pairs with only one proband are further investigated and additional concordant pairs are thus discovered. A mathematical model is presented that allows for continuous variation in completeness of ascertainment in both stages, for correlation within pairs in the primary ascertainment process, and for correlation within pairs in occurrence of the disease. The concordance rate can be estimated by the proband method if secondary ascertainment is complete; other measures of concordance are accurate only if primary ascertainment is complete. A parameter analogous to the concordance rate but related to correlation in primary ascertainment can be estimated from the same data.
The use of epidemiological studies of twins as a means of determining the existence of genetic factors in various conditions is well known. To be of value, the zygosity of the twin pairs must be identified with as great a degree of confidence as possible. A method of determining twin zygosity, using concordance in general likeness, hair colour, hair type, eye colour, ear form, tongue roll and phenylthiocarbamide (PTC) taste sensitivity, was developed for use in a survey of 244 pairs of like-sexed twins aged 5 to 15 years. The results obtained and the problems raised when applying this method are discussed. The method was sinple to apply to a large group of twin pairs, and monozygotic pairs were identified with a degree of confidence greater than 95%.
In comparing the strength of a trait disease association among discordant monozygotic vs. discordant dizygotic twins, the zygosity group showing a lower proportion of discordance for the trait will have a greater reduction of the apparent association by dilution. When, as usually happens, the monozygotics have a lower proportion of discordance, the genetic hypothesis will be falsely supported. If individual twins with a given trait and with discordant co twins are compared with individual twins with the same trait but with concordant co twins (e.g., nonsmokers with smoking co twins compared with nonsmokers with nonsmoking co twins), those with discordant co twins will tend to resemble those with the opposite trait, partially because a greater proportion actually have the opposite trait. That is, nonsmokers with smoking co twins will tend to resemble smokers more than do nonsmokers with non smoking co twins, at least partially because a greater proportion of the former are actually smokers. As a practical approach to the problem the author suggests that extra efforts be made to verify the characteristics of apparently discordant twins. For example, a followup questionnaire could be sent to those twins reporting discordance on a first questionnaire. Studies of discordant twins offer the epidemiologist a valuable method for dissecting out disease causing factors. Efforts should be directed at making them as accurate and useful as possible.
Genetic models are described which exploit the unique relationships that exist within the families of identical twins to obtain weighted least squares estimates of additive, dominance and epistatic components of genetic variance as well as estimates of the contributions of X-linked genes, maternal effects and three sources of environmental variation. Since all of the relationships required to achieve a resolution of these variance components are contained within each family unit, the model would appear to be superior to previous approaches to the analysis of quantitative traits in man.
Cholesterol levels were measured in the cord blood of 30 pairs of monochorionic and 22 pairs of dichorionic monozygotic (MZ) twins. Cholesterol levels were found to be significantly higher in female twins when data was combined over chorion type. The type of chorionic development had no significant effect on variation among twin pairs. Chorion type did, however, have a significant effect on the within-pair variation. The variation within dichorionic pairs was more than five times that within monochorionic pairs (P less than .01). This result suggests that the variation in placentation has a significant effect on within-pair variation in serum cholesterol of newborn MZ twins.
Suppose that L like-sexed and U unlike-sexed twins have been observed. Weinberg's method estimates the numbers of DZ and MZ twins as DZ = 2U and MZ = L--U. This method is based on the assumptions that (1) the sex ratio in DZ twins is 1/2 and (2) the sexes of DZ twins are determined independently and with the same probability in all parents; in consequence there should, on average, be equal numbers of like-sexed and unlike-sexed DZ twins. The first assumption is not exactly true, but the necessary correction is negligible. Departures from the second assumption would probably lead to an excess of like-sexed over unlike-sexed DZ twins; in consequence, Weinberg's method would underestimate the numbers of DZ twins and overestimate the numbers of MZ twins. The literature on the frequencies of like-sexed and unlike-sexed pairs among twins known to be DZ through other genetic markers is reviewed. It is concluded that there is no evidence of an excess of like-sexed twins among them, and that there is therefore no reason to doubt the validity of Weinberg's method. The extension of Weinberg's method to estimate the zygosity types of triplets and quadruplets is described; it is shown that the resulting estimates agree well with the results of direct zygosity determination by blood grouping.
Blood pressures in 200 pairs of twins having a mean age of 14.0 (S.D. equals 6.5) years were measured at basal levels and in response to the cold pressor test. Intraclass correlations were consistently larger (and intrapair variances consistently smaller) in monozygotic as compared to dizygotic pairs, substantially more so in females than in males. Sex differences in heritability were somewhate greater for systolic than for diastolic blood pressure. Indices of heritability (H) at basal levels were, in descending order: 0.78 (female systolic), 0.61 (female diastolic), 0.56 (male diastolic), and 0.41 (male systolic). The same descending order for H was found for blood pressure responses to the cold pressor test. It is concluded that in the population studied, genetic factors play an important role in the control of blood pressure over the normal range of vascular reactivity. In females, such factors may be the major determinant of the variability observed.
Many factors both genetic and environmental contribute to the liability to coronary heart disease and one of the genetically determined risk factors is the concentration of lipoproteins in the blood. The evidence so far is that serum cholesterol level is polygenically determined, but that in a minority of the population it is determined by a single mutant gene of large effect. There is evidence that the risk of coronary death for affected individuals is very high and that the condition warrants a maximum effort at identification and treatment. For the remainder of the population whose hyperlipidaemia is polygenically determined, the liability to coronary heart disease might be substantially reduced by simple and appropriate environmental measures aimed at reducing the total liability. The measures if correctly applied should effectively improve the population risks of early coronary death.
The Swedish Twin Registry contains about 11 000 same-sexed twin pairs born between 1886 and 1925 with both members alive when the registry was formed in 1961. During the years 1962 to 1973, 2780 deaths occurred. 727 deaths were due to ischaemic heart disease (IHD), 345 due to cerebrovascular disease (CVD), and 727 due to cancer. The rate of concordance for the whole twin population revealed a significantly (p < 0.05) higher concordance rate for IHD among the male monozygotic (MZ) pairs as compared to the dizygotic (DZ) pairs (15.8% versus 8.0%). The corresponding figures for the female pairs were 11.0% (MZ) and 7.5% (DZ), respectively. With regard to death in CVD and cancer, the rates of concordance were about the same for MZ and DZ pairs in both males and females. When subgrouping was made for age groups, the difference in concordance rate for IHD in males was still more pronounced for the younger age group, born 1901–1925, (16.1% versus 5.4%). These data may indicate the existence of a genetic determination on death in IHD, especially in males, whereas a genetic determination on death in CVD and cancer seems more uncertain.
Data obtained in a study of mentally defective twins permitted the examination of interdependence and efficiency of blood groups and fingerprints in zygosity diagnosis. After exclusion of Down's syndrome, the series consisted of 49 MZ pairs, 52 DZ pairs and 18 pairs of uncertain type.
Same-sex pairs discordant for Down's syndrome seemed to include some pairs of uniovular or irregular origin, but this could not be investigated cytologically. Concordance appeared to occur independently in different blood group systems. However, DZ twins concordant in the ABO blood groups were significantly more similar in their fingerprints than were other pairs, and the within-pair differences were more uniform.
Linear discriminant functions designed for zygosity diagnosis make much better use of dermatoglyphic information than do simpler measures, and the latter could not be much improved by comparing left and right hands separately.
Proband concordance rates in twins provide estimates of correlation among twins in liability to a trait or condition. The correlations in turn can be interpreted genetically by the expression 2(r(MZ)-r(DZ)) which eliminates nongenetic familial effects on twins and estimates the coefficient of genetic determination for the trait. The rates of diagnosis and of ascertainment of individuals and their cotwins must also be taken into account, along with other factors such as differences in frequency between sexes, variable age of onset, and variable expressivity or severity. A set of rules for the minimal set of data required and for a standard form of analysis is presented. The genetic interpretation of other measures of concordance is difficult and their value is questionable. The indices of 'heritability' proposed by Holzinger, widely used by human geneticists, are shown to be unsatisfactory and their use should be discontinued.
Population differences in heritability of IQ scores were found for racial and social class groups.
Important works on the question of hereditary influence on the occurrence of cancer with application of twin series are those by v. Verschuer and Kober (cf. Spranger and v. Verschuer, 1964), Jarvik and Falek (1961) and Harvald and Hauge (1963). Their findings are by and large consistent with most earlier reports (Schull et al, 1959) and indicate that hereditary factors do not seem to influence the development of cancer as such, but possibly play a role in the localization of the tumor. In view of the fact that (except for Harvald and Hauge's investigation) the twin series studied have been comparatively small and yielded statistically unreliable numbers of cancer of specific site, it seems to be of value to extend the data by reporting findings from the Swedish Twin Registry, comprising about 11000 unselected twin pairs.
The present paper reports mortality and morbidity in cancer of different site as well as concordance rates for MZ and DZ twins. In addition, the influence of smoking habits on cancer development has been analyzed, as this environmental factor is known to be associated with certain forms of cancer, particularly lung cancer (Smoking and Health, 1964).
Cancer data have been obtained from two sources, the Swedish Cancer Registry and the Registry of Causes of Death.
The Swedish Twin Registry in the present report comprises 10 945 twin pairs, and covers, in principle, all same-sexed twins born in Sweden in 1886-1925, and still living in the country as unbroken pairs at the time of compilation (1961). A detailed report of the compilation procedures and demographic data is given by Cederlöf (1966).
It seems to be generally accepted that genetic factors take a place among the causes of coronary heart disease. Careful and extensive family studies, among others by workers in Carter's group, have shown that the risk to close relatives of patients with coronary heart disease is significantly increased. This may, however, be an effect of the common social background in families. Systematic twin investigations have been needed, which could distinguish between the effects of common environment and common genes, and allow an estimate of the relative importance of genetic and environmental factors.
The present study is an approach to this problem by using twins with coronary heart disease in the Danish Twin Register (Hauge et al, 1968). This was founded in 1954 and has been developed ever since. It now contains total medical information on about 10 000 unselected pairs of twins born in Denmark in the period 1870-1910, where both partners have survived the age of five. On January 1, 1968, coronary occlusion had been registered in a total of 352 twins.
The Danish Twin Register, which comprises all twins born in Denmark between 1870 and 1920, has been used for studies of selected problems in the field of epidemiology and public health. This report gives a survey of the preliminary results of an investigation of this type, which intends to amplify the present knowledge about the possible harmful effects of smoking on health, by taking advantage of a twin material which makes it possible to keep the genetic factors under control.
A series of 762 MZ and same-sexed DZ twin pairs, which had their smoking habits mapped in 1959, has been followed continuously, and the mortality which has occurred in this group has been analysed in relation to tobacco consumption. Neither MZ nor DZ pairs showed any tendency to increased mortality in the heavier smoking cotwins. When the material was subdivided according to cause of death, no conspicuous exception from the general pattern was found, but the subgroups were relatively small.
The distribution of selected diseases and symptoms, mainly of the cardiovascular and respiratory systems, was studied in this and a second series, followed since 1966, with a total of 1584 pairs.
1. The Author has investigated on a twin material of 34 twin pairs the papillary line patterns on the fingers, the interdigital areas of the palms, and the hallucal area of the soles according to a systematics accounted for by the Author in earlier works.
2. The diagnosis of zygosity has been based on a comparison for the morphological particularities and on blood group analyses, in the cases in which the relative chance for dizygosity for the concordant pairs has been calculated.
3. The frequency distribution for the papillary line patterns of the twin pairs showed no significant divergence with respect to the large Swedish population, earlier investigated.
4. The 19 MZ twin pairs showed a concordance of 84.2-89.5% for the total qualitative value, total ridge-count and for the hallucal patterns.