Chinese National Twin Registry as a resource for genetic epidemiologic studies of common and complex diseases in China.

Twins, due to their unique genetic and environmental relationships, have provided crucial insight in our understanding of genetic contributions to numerous etiologically complex disorders in developed countries. As the leading cause of death and adult disability, cardio- and cerebrovascular diseases are common in China, followed by cancer. Obesity and psychological disorders are increasing. The overall goal of this program is to develop a resource for genetic epidemiologic studies of these and other common and complex diseases in China. Our initial focus is to delineate the genetic and environmental determinants of vascular diseases in general, coronary artery disease (CAD) and stroke in particular. To date, we have over 4500 twin pairs registered and about 700 twin pairs studied for various metabolic traits (e.g., lipids, glucose, insulin, etc.). The long-term plan of this program is to (1) establish a population-based twin registry from several selected regions in China for future studies of specific common complex diseases; (2) conduct detailed phenotyping for clinical and intermediate traits related to cardiovascular diseases; (3) expand studies of twins to twin families by including their parents, siblings, and offspring for genetic linkage and association studies; and (4) follow up twins in the registry longitudinally. The goals of the program are health education and promotion of healthy behavior, early identification of cases to provide timely medical attention, and the evaluation of long-term effects of identified risk factors. We want to develop collaborations with investigators who have expertise in cancer, psychological disorders, and other disease areas.     

Twins and non-twin siblings: different estimates of shared environmental influence in early childhood.

Twin studies typically indicate shared environmental influence for cognitive abilities, especially in early childhood. However, across studies, DZ twin correlations tend to be greater than non-twin sibling correlations, suggesting that twin estimates of shared environment are to some extent specific to twins. We tested this hypothesis in a sample of more than 1800 MZ and 1800 same-sex DZ pairs from the Twins Early Development Study (TEDS), a study of twins born in England and Wales in 1994 and 1995. For this analysis, we obtained comparable data from more than 130 same-sex younger siblings of the twins. Twins and their younger siblings were assessed for language, cognitive abilities and behavior problems by their parents at 2 and 3 years of age. For language and cognitive measures at both 2 and 3 years, but not for behavior problems, estimates of shared environment were more than twice as large for twins as compared to non-twin siblings. We conclude that about half of twin study estimates of shared environment for cognitive abilities in early childhood are specific to twins. Although many possibilities exist for explaining the special shared environment effect for twins, we suggest that cognitive-relevant experiences that are not shared by siblings are shared by twins because they are exactly the same age.     

A twin study of genetic and environmental influences on psychological traits of eating disorders in a Japanese female sample.

The purpose of the present study was to clarify genetic and environmental origins of psychological traits of eating disorders using a Japanese female twin sample. Participants were 162 pairs of female twins consisting of 116 pairs of monozygotic (MZ) twins and 46 pairs of dizygotic (DZ) twins in their adolescence. Psychological traits of eating disorders were assessed with five subscales of the Eating Disorder Inventory (EDI). As a result of using univariate twin analyses, among five subscales of EDI (maturity fears, ineffectiveness, interpersonal distrust, interoceptive awareness, and perfectionism), perfectionism showed significant additive genetic contributions and individual specific environmental effects. On the other hand, maturity fears, ineffectiveness, interoceptive awareness, and interpersonal distrust indicated significant shared environment contributions and individual specific environment effects. The results suggest the importance of both genetic and shared environmental influences on psychological traits of eating disorders in the present study.     

The mechanism of emergenesis

Since each individual produced by the sexual process contains a unique set of genes, very exceptional combinations of genes are unlikely to appear twice even within the same family. E. O. Wilson (1978)The intraclass correlations of monozygotic twins who were separated in infancy and reared apart (MZA twins) provide estimates of trait heritability, and the Minnesota Study of Twins Reared Apart [MISTRA: Bouchard et al. (1990), The sources of human psychological differences: the Minnesota study of twins reared apart, Science 250, 223-228] has demonstrated that MZA pairs are as similar in most respects as MZ pairs reared together. Some polygenic traits--e.g. stature, IQ, harm avoidance, negative emotionality, interest in sports--are polygenic-additive, so pairs of relatives resemble one another on the given trait in proportion to their genetic similarity. But the existence and the intensity of other important psychological traits seem to be emergent properties of gene configurations (or configurations of independent and partially genetic traits) that interact multiplicatively rather than additively. Monozygotic (MZ) twins may be strongly correlated on such emergenic traits, while the similarity of dizygotic (DZ) twins, sibs or parent-offspring pairs may be much less than half that of MZ pairs. Some emergenic traits, although strongly genetic, do not appear to run in families. MISTRA has provided at least two examples of traits for which MZA twins are strongly correlated, and DZA pairs correlate near zero, while DZ pairs reared together (DZTs) are about half as similar as MZTs. These findings suggest that even more traits may be emergenic than those already identified. Studies of adoptees reared together (who are perhaps more common than twins reared apart) may help to identify traits that are emergenic, but that also are influenced by a common rearing environment.     

Twins early development study (TEDS): a multivariate, longitudinal genetic investigation of language, cognition and behavior problems in childhood.

The Twins Early Development Study (TEDS) focuses on the early development of the three most common psychological problems in childhood: communication disorders, mild mental impairment and behavior problems. The TEDS twins were assessed longitudinally at 2, 3, 4 and 7 years of age in order to investigate genetic and environmental contributions to change and continuity in language and cognitive development; it is multivariate in order to examine the origins of comorbidity; and it uses a large sample in order to study abnormal development in the context of normal development. The twins were identified from birth records of twins born in the UK in 1994-96. More than 15,000 pairs of twins have been enrolled in TEDS and the participating families are representative of the UK. The measures at 2, 3 and 4 years are administered by parents. At 7 years, children are assessed for language and cognitive development using telephone testing, parents and children are interviewed about behavior problems, and teachers also assess behavior problems as well as academic achievement. One set of findings is that the same genes largely contribute to both language and cognitive problems and the same genes affect normal and abnormal development, a result that suggests that general impairment may be a better target for genetic research than specific language impairment independent of nonverbal cognitive problems. DNA has been obtained so far for more than 4000 pairs and is being used initially in molecular genetic studies of language problems and hyperactivity.     

A longitudinal genetic analysis of low verbal and nonverbal cognitive abilities in early childhood.

By middle childhood, the same genetic factors are largely responsible for individual differences in verbal and nonverbal abilities, suggesting a genetic basis for general cognitive ability ("g"). Our previous work on verbal and nonverbal abilities throughout the normal range of variation during infancy and early childhood suggests that genetic influences show domain-specific as well as domain-general effects, implying that the switch to nearly complete domain-general effects occurs later in development. Much less is known about the genetic structure of low cognitive performance, although our previous work has shown that a composite measure of low "g" is highly heritable at 2, 3 and 4 years of age. We report the first multivariate, longitudinal analyses of low verbal and nonverbal cognitive abilities (defined as the lowest 10% of the distribution) at 2, 3 and 4 years of age using data from 9026 pairs of UK twins assessed by their parents as part of the Twins Early Development Study (TEDS). Domain-general genetic influences increased significantly from 2 to 3 to 4 years. Although the phenotypic polychoric correlation between low verbal and low nonverbal ability was similar at 2, 3 and 4 years (.36,.43,.35), the genetic contribution to the phenotypic correlation increased dramatically (.37,.47,.76), with a corresponding decrease in the comorbid influence of shared environment (.61,.44,.35). We conclude that for low ability, as well as for normal variation in ability, genetic "g" emerges during early childhood but is not fully developed until middle childhood.     

Long-term effect of placental type on anthropometrical and psychological traits among monozygotic twins: a follow up study.

The long-term effect of differences in placentation in MZ twins is a controversial subject. An effect has been clearly established for birth weight but data on psychological traits are still under debate. We studied 20 pairs of monochorionic MZ (MC MZ) and 24 pairs of dichorionic MZ (DC MZ) twins. A chorion effect was observed for Block Design (WISC-R) confirming a previous report: MC MZ co-twins were more similar that DC MZ co-twins. For anthropometrical measures, an expected effect in the opposite direction was found. No chorion effect was significant for the other variables. A follow up was undertaken 3 years later using cognitive, national academic evaluations, and personality variables. The sample included 16 pairs of MC MZ and 22 pairs of DC MZ twins. Again a chorion effect was observed on anthropometrical variables but results on the Block Design were not replicated. However, the MC MZ co-twins were more similar than the DC MZ co-twins for two other cognitive variables: Perceptual Organization Index from the WISC-R and Global Visualisation from a Belgian reasoning test. Among the personality variables only one was sensitive to a chorion effect. The discussion focuses on the need for larger samples to achieve adequate power in statistical comparisons.     

Genetic Influences Are Virtually Absent for Trust

Over the past decades, numerous twin studies have revealed moderate to high heritability estimates for individual differences in a wide range of human traits, including cognitive ability, psychiatric disorders, and personality traits. Even factors that are generally believed to be environmental in nature have been shown to be under genetic control, albeit modest. Is such heritability also present in social traits that are conceptualized as causes and consequences of social interactions or in other ways strongly shaped by behavior of other people? Here we examine a population-based sample of 1,012 twins and relatives. We show that the genetic influence on generalized trust in other people (trust-in-others: h² = 5%, ns), and beliefs regarding other people’s trust in the self (trust-in-self: h² = 13%, ns), is virtually absent. As test-retest reliability for both scales were found to be moderate or high (r = .76 and r = .53, respectively) in an independent sample, we conclude that all variance in trust is likely to be accounted for by non-shared environmental influences. We show that, relative to cognitive abilities, psychiatric disorders, and classic personality variables, genetic influences are smaller for trust, and propose that experiences with or observations of the behavior of other people shape trust more strongly than other traits.     

同卵双胞胎在复杂性状DNA甲基化调控机制研究中的应用

同卵双胞胎来源于同一个受精卵,DNA序列基本一致,但在某些重要表型上如复杂疾病,并不完全一样。利用表型不一致的同卵双胞胎进行研究,能在遗传背景、母体效应、年龄性别效应等一致的基础上,深入研究分析复杂性状的表观调控机制。而DNA甲基化是最为稳定的一类表观遗传修饰。在人类中,利用同卵双胞胎对印记异常疾病、精神类疾病、自身免疫病及癌症等疾病的DNA甲基化调控研究已经揭示了多个致病基因,为研究疾病的表观调控以及表观遗传学药物的应用打下了基础。本文着重对同卵双胞胎DNA甲基化状态、DNA甲基化遗传力计算以及复杂性状DNA甲基化调控的研究应用及其进展展开综述,以期为复杂性状表观调控机制研究提供借鉴和参考。     

The personalities of twins: just ordinary folks.

Twin studies have demonstrated that personality traits show moderate genetic influence. The conclusions drawn from twin studies rely on the assumptions that twins are representative of the population at large and that monozygotic and dizygotic twins are comparable in every way that might have bearing on the traits being studied. To evaluate these assumptions, we used Multidimensional Personality Questionnaire (MPQ) data from three samples drawn from the Minnesota Twin Registry (totaling 12,971 respondents) to examine the effect sizes associated with mean differences on the 11 MPQ scales and 3 higher-order MPQ factors for singletons versus twins and MZ twins versus DZ twins. The singletons in the samples were family members of the participating twins. We also used ratios of scale variances to examine the significance of variance differences. The only mean or variance difference replicated across all three samples was greater Social Closeness (about.1 standard deviation) for twins than for singletons. This difference was obtained for both males and females. It would appear that, with respect to personality, twins are not systematically different from other people. Our results also highlight the importance of replication in psychological research because each of our large samples showed differences not replicated in other samples.     

Human behavioural genetics of cognitive abilities and disabilities

Although neither the genome nor the environment can be manipulated in research on human behaviour, some of the new tools of molecular genetics can be brought to bear on human behavioural disorders (e.g. cognitive disabilities) and quantitative traits (e.g. cognitive abilities). The inability to manipulate the human genome experimentally has had the positive effect of focusing attention on naturally occuring genetic variation responsible for behavioural differences among individuals in all their complex multifactorial splendour. Genes in such complex multiple-gene systems are called quantitative trait loci (QTLs), which merge the two worlds of genetic research, quantitative genetics and molecular genetics. Although most genetic research on complex human behaviour has focused on severe mental disorders, cognitive abilities and disabilities may be even more immediately relevant to neuroscience. For example, verbal ability and spatial ability are two of the most heritable cognitive abilities, and reading disability is the first behavioural disability for which replicated QTL linkage has been found. The purpose of this essay is to provide an overview of the genetics of cognitive abilities and disabilities as an example of the impending merger of quantitative genetics and molecular genetics in QTL analysis of complex traits.     

Netherlands Twin Register: a focus on longitudinal research.

In 1986 we began The Netherlands Twin Register (NTR) by recruiting young twins and multiples a few weeks or months after birth. Currently we register around 50% of all newborn multiples in The Netherlands. Their parents receive a questionnaire at registration and afterwards when the children are 2, 3, 5, 7, 10 and 12 years of age. Teachers are asked to rate the behavior of the children at ages 7, 10 and 12 years. Adolescent and young-adult twins were recruited through City Councils in the early 1990s. These twins, their parents and siblings participate in longitudinal survey studies that include items about health, fertility, lifestyle, addiction, personality and psychopathology, religion, socioeconomic status, and educational attainment. The total number of twins and multiples registered with the NTR is currently over 60,000. Subgroups of twins and siblings take part in studies of cognitive development, brain function and neuropsychological indices of attention processes, and molecular genetic studies of classical and behavioral cardiovascular risk factors. DNA samples are currently collected in selected twin families for two large linkage studies, which aim to find QTLs for anxious depression and for nicotine addiction. Sisters who are mothers of DZ twins contribute DNA samples for a linkage study of DZ twinning. Large cohorts of phenotyped family members from the general population are very valuable for genetic epidemiological studies and permit selection of informative families for gene finding studies.     

Chorion type as a possible influence on the results and interpretation of twin study data.

The estimation of genetic effects from twin studies usually relies upon the equal environment assumption--that monozygous (MZ) and dizygous (DZ) twin pairs experience equal similarity of their environments from prenatal experiences through adulthood. However, the sharing of a chorion may make a subset of identical twins more similar, or in some cases, more different, than twins that do not share a chorion. Recent studies suggest monochorionic MZ twins resemble one another more than dichorionic MZ twins in cognitive abilities, personality, and risk for psychiatric disorder. To the extent that prenatal environment affects these characteristics, the traditional twin method will yield biased estimates of genetic and environmental influences. We develop models for quantifying this bias and estimating the influence of chorion type on estimates of heritability.     

Twin-Based DNA Methylation Analysis Takes the Center Stage of Studies of Human Complex Diseases

The etiology of complex diseases is characterized by the interaction between the genome and environmental conditions and the interface of epigenetics may be a central mechanism. Current technologies already allow us high-throughput profiling of epigenetic patterns at genome level. However, our understanding of the epigenetic processes remains limited. Twins are special samples in genetic studies due to their genetic similarity and rearing-environment sharing. In the past decades, twins have made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable samples of twins are helping to bridge the gap between gene activity and environmental conditions through epigenetic mechanisms unlimited to DNA sequence variations. We review the recent progresses in using twins to study disease-related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Various study designs and application issues will be highlighted and discussed with aim at making uses of twins in assessing the environmental impact on epigenetic changes during the development of complex diseases.     

Social jetlag,academic achievement and cognitive performance: Understanding gender/sex differences

Adolescents in high school suffer from circadian misalignment, undersleeping on weekdays and oversleeping on weekends. Since high schools usually impose early schedules, adolescents suffer from permanent social jetlag (SJL) and thus are a suitable population to study the effects of SJL on both academic and cognitive performance. In this study, 796 adolescents aged 12–16 years reported information about their sleep habits, morningness–eveningness (M–E), cognitive abilities and grade point average (GPA). Time in bed on both weekdays and weekends was not related to cognitive abilities, and only time in bed on weekdays was related to academic achievement. SJL was negatively related to academic achievement, cognitive abilities (except for vocabulary and verbal fluency abilities) and general cognitive ability (g), whereas M–E was slightly positively related to academic achievement and marginally negatively related to inductive reasoning. Results separated by sex/gender indicated that SJL may be more detrimental to girls’ performance, as it was negatively related to a greater number of cognitive abilities and GPA.     

How general is cognitive ability in non-human animals? A meta-analytical and multi-level reanalysis approach

General intelligence has been a topic of high interest for over a century. Traditionally, research on general intelligence was based on principal component analyses and other dimensionality reduction approaches. The advent of high-speed computing has provided alternative statistical tools that have been used to test predictions of human general intelligence. In comparison, research on general intelligence in non-human animals is in its infancy and still relies mostly on factor-analytical procedures. Here, we argue that dimensionality reduction, when incorrectly applied, can lead to spurious results and limit our understanding of ecological and evolutionary causes of variation in animal cognition. Using a meta-analytical approach, we show, based on 555 bivariate correlations, that the average correlation among cognitive abilities is low (r = 0.185; 95% CI: 0.087–0.287), suggesting relatively weak support for general intelligence in animals. We then use a case study with relatedness (genetic) data to demonstrate how analysing traits using mixed models, without dimensionality reduction, provides new insights into the structure of phenotypic variance among cognitive traits, and uncovers genetic associations that would be hidden otherwise. We hope this article will stimulate the use of alternative tools in the study of cognition and its evolution in animals.     

Great minds think different: Preserving cognitive diversity in an age of gene editing

It is likely that gene editing technologies will become viable in the current century. As scientists uncover the genetic contribution to personality traits and cognitive styles, parents will face hard choices. Some of these choices will involve trade-offs from the standpoint of the individual's welfare, while others will involve trade-offs between what is best for each and what is good for all. Although we think we should generally defer to the informed choices of parents about what kinds of children to create, we argue that decisions to manipulate polygenic psychological traits will be much more ethically complicated than choosing Mendelian traits like blood type. We end by defending the principle of regulatory parsimony, which holds that when legislation is necessary to prevent serious harms, we should aim for simple rules that apply to all, rather than micro-managing parental choices that shape the traits of their children. While we focus on embryo selection and gene editing, our arguments apply to all powerful technologies which influence the development of children.     

Twin-singleton differences in intelligence?

The twin method has been criticised for its alleged non-generalisability. When population parameters of intellectual abilities are estimated from a twin sample, critics point to the twin-singleton differences in intrauterine and family environments. These differences are suggested to lead to suboptimal cognitive development in twins. Although previous studies have reported twin-singleton differences in intelligence, these studies had two major drawbacks: they tested young twins, and twins were compared with (genetically) unrelated singletons. To test accurately whether twin-singleton differences in intelligence exist, a group of adult twins and their non-twin siblings were administered the Dutch WAIS-III. The group was large enough to detect twin-singleton differences of magnitudes reported in earlier investigations. The data were analysed using maximum likelihood model fitting. No evidence of differences between adult twins and their non-twin siblings on cognitive performance was found. It is concluded that twin studies provide reliable estimates of heritabilities of intellectual abilities which can be generalised to the singleton population.     

Generalist genes and the Internet generation: etiology of learning abilities by web testing at age 10

A key translational issue for neuroscience is to understand how genes affect individual differences in brain function. Although it is reasonable to suppose that genetic effects on specific learning abilities, such as reading and mathematics, as well as general cognitive ability ( g ), will overlap very little, the counterintuitive finding emerging from multivariate genetic studies is that the same genes affect these diverse learning abilities: a Generalist Genes hypothesis. To conclusively test this hypothesis, we exploited the widespread access to inexpensive and fast Internet connections in the UK to assess 2541 pairs of 10-year-old twins for reading, mathematics and g , using a web-based test battery. Heritabilities were 0.38 for reading, 0.49 for mathematics and 0.44 for g . Multivariate genetic analysis showed substantial genetic correlations between learning abilities: 0.57 between reading and mathematics, 0.61 between reading and g , and 0.75 between mathematics and g , providing strong support for the Generalist Genes hypothesis. If genetic effects on cognition are so general, the effects of these genes on the brain are also likely to be general. In this way, generalist genes may prove invaluable in integrating top-down and bottom-up approaches to the systems biology of the brain.     

Genetic influences on ‘environmental’ factors

Childhood environment, social environment and behavior, leisure time activities and life events have been hypothesized to contribute to individual differences in cognitive abilities and physical and emotional well‐being. These factors are often labeled ‘environmental’, suggesting they shape but not reflect individual differences in behavior. The aim of this study is to test the hypothesis that these factors are not randomly distributed across the population but reflect heritable individual differences. Self‐report data on Childhood Environment, Social Environment and Behavior, Leisure Time Activities and Life Events were obtained from 560 adult twins and siblings (mean age 47.11 years). Results clearly show considerable genetic influences on these factors with mean broad heritability of 0.49 (0.00–0.87). This suggests that what we think of as measures of ‘environment’ are better described as external factors that might be partly under genetic control. Understanding causes of individual differences in external factors may aid in clarifying the intricate nature between genetic and environmental influences on complex traits.