Introduction - Reading PDF

Introduction - Reading 08 October 2023 01:49 Source Notes The continuing value of twin studies in the omics era (van Dongen et al., 2012) The classical twin design Has been used for decades to estimate the importance of genetic and environmental influences on complex trait variation. Results have co...

Introduction - Reading 08 October 2023 01:49 Source Notes The continuing value of twin studies in the omics era (van Dongen et al., 2012) The classical twin design Has been used for decades to estimate the importance of genetic and environmental influences on complex trait variation. Results have contributed to the awareness that variation in almost every conceivable facet of the human condition is influenc ed by genetic variation. Traits include intrinsic physical, medical and biochemical characteristics, life -outcome variables, such as income, divorce and mortality, and behavioural traits, including apparently trivial ones such as television watching and Internet use. Through their collaboration in genome-wide association study (GWAS) consortia, large twin registries are nowadays also making an important contribution towards ide ntifying the genetic variation that underlies complex traits and disorders. Twins offer unique opportunities to genetic research that extend beyond the analysis of phenotypic heritability: ○ Twin designs can provide insight into the genetic aetiology of disease development over time and can aid in the detection of biomarker profiles for medical conditions. ○ For heritable traits, the comparison of discordant monozygotic twins (discordant MZ twins) represents a powerful improvement over the traditional case–control study to search for disease-associated biological marks. ○ Novel applications of the classical twin design can provide fundamental insights into the biological mechanisms underlying complex traits. For example, gene expression studies in MZ and dizygotic (DZ) twins have highlighted that variation in genome-wide expression between individuals is due to both genetic and environmental influences and that the importance of these influences may vary across genes and tissues. The history of the classical twin study The scientific study of twins goes back to 1875, when Francis Galton published his seminal paper "The history of twins, as a criterion of the relative powers of nature and nurture." However, Galton was unaware of the distinction between monozygotic (MZ) and dizygotic (DZ) twins. The first studies that investigated the different levels of similarity between MZ and DZ twins were published by Poll (1914) and Siemens (1924), whose interest was pigmented nevi (common moles), a phenotype that is still being studied intensively today because of its importance as a risk factor for melanoma. Not much later, the first twin registries were founded, and power calculations showing that very large sample sizes were need ed to obtain reliable estimates of heritability stimulated the foundation of new large registries in the 1980s. Consolidation of these registries, new methods for zygosity assessment and improved survey methods coincided with a growing a wareness that genetic influences affected a wide range of traits of biomedical and social importance, and an increase in funding to mount large studies. Worldwide, many countries have now set up twin registries, which have established collections of longitudinal data in twins a cross age categories from birth to death. Within the past 20 years, very large twin studies have been carried out through mailed, telephone and Internet surveys. Methods linking twin registry data to national databases containing information on cancer and mortality, or outcomes of popul ation screens, have provided population-based estimates of heritability on samples as large as 44,000 twin pairs. The continuing importance of twin study designs Quantitative analysis of genetic and environmental influences ○ Twin studies can be used to estimate the heritability of traits, which is the proportion of the variation in a trait that is due to genetic factors. ○ Twin studies can also be used to estimate the extent to which different traits are influenced by the same or different genetic and environmental factors. ○ Twin studies can also be used to model polygenic G×E interactions, or how the heritability of a trait varies across different levels of environmental exposures. ○ Twin studies can be extended to include data from other relatives, such as parents, siblings, spouses, and offspring, to increase statistical power and test a wider range of hypotheses about the causes of human variation. ○ Twin studies can be used to establish the proportion of the heritability of a trait that can be explained by newly identified SNPs from genome-wide association studies (GWASs). The value of discordant twins ○ Data from MZ and DZ twins can be used to examine causal relationships in the comorbidity of traits. This is done using a design called the co-twin control method. ○ The co-twin control design can be used to distinguish between associations that reflect causality and associations owing to confounding effects of genes or environmental factors. Examples of recent studies using twin designs ○ A twin study found that the relationship between exercise behavior and depression was explained by shared genetic influences rather than by a cause–effect relationship. ○ A twin study revealed a reciprocal causal relationship between depression and migraine. ○ A co-twin control study of anthropometric traits and cancer found a positive correlation between height and risk of breast and ovarian cancers and indicated correlations between BMI and several types of cancer in some population subgroups. ○ The comparison of discordant MZ twins offers an alternative to the traditional case–control study ○ primary interest is not to infer causality but to identify factors associated with a trait of interest that differ between cases and controls who are perfectly matched for age, sex and genetic background, and who are partly matched for early environmental influence Molecular phenotypes and the causes of quantitative trait variation The power of twin studies for studying molecular biology Twin studies can be used to study molecular phenotypes, such as gene expression levels, DNA methylation, and metabolite conce ntrations. Twin studies can be used to identify the genetic and environmental factors that influence molecular variation. Twin studies can be used to study gene-by-environment interactions and transgenerational inheritance of epigenetic regulation. Twin studies can be used to identify biomarkers of ageing and disease. Tracing the origin of new mutations Twin studies can be used to identify somatic mutations that occur after twinning. Twin studies can be used to study the role of copy number variations (CNVs) in disease. Twin studies can be used to study the role of de novo mutations in disease. Example studies: A twin study found that telomere length at advanced age is predictive of survival. A twin study found evidence for a pre-twinning de novo duplication in a healthy twin pair and a post -twinning de novo deletion in one twin from a pair of twins who were concordant for attention problems. A twin study found no evidence for structural genomic differences between MZ twins who were discordant for congenital diaphra gmatic hernia and oesophageal atresia. A twin study applied whole-genome-sequencing technology in discordant MZ twins and found that only a small fraction of SNPs and structural variants differed wi thin twin pairs. Timing the occurrence of de novo mutations Twin studies can be used to track the developmental timing of de novo mutations if DNA from multiple cell lines is available for both twins. For any disease caused by de novo mutations, information about the timing of mutagenesis is of major importance for genetic c ounselling. Phenotypic impact of epigenetic variation Epigenetic variation may be another important source of phenotypic variation and discordance in MZ twins. DNA methylation and gene expression studies in discordant MZ twins have identified epigenetic changes associated with a varie ty of diseases, including Alzheimer's disease, autism, bipolar disorder, birth weight, cancer, and SLE. Twin studies can also be used to study the heritability of epigenetic variation. Differential miRNA expression and disease miRNA expression studies in discordant MZ twins have identified differential expression of miRNAs associated with autism and lupus nephritis. Gene expression: causes and disease links Twin studies can be used to identify expression quantitative trait loci (eQTLs) and gene expression alterations associated wi th various disease states. Twin studies can also be used to study the effects of drug therapies on gene expression. The classical twin design The classical twin design is used to estimate the genetic and environmental influences on phenotypic variation. Phenotypic variation (VP) is decomposed into genetic variance (VG) and environmental variance (VE): VP=VG+VE. Genetic variance is further decomposed into additive genetic variance (VA) and variance due to non -additive genetic effects (dominance variance (VD)): VG=VA +VD. Narrow-sense heritability (h2) is the proportion of variation that is due to additive genetic variance: h2=VA /VP. Environmental influences are comprised of shared environmental influences (VC) and unique environmental influences (VU): VE=V C +VU. Genetic structural equation modelling (GSEM) is used to estimate variance components from twin data. GSEM obtains maximum likelihood estimates of variance components by comparing the expected MZ and DZ covariances to the covar iances observed in the data. With MZ and DZ data, VC and VD cannot be estimated simultaneously. VD is estimated if there is stronger evidence for non -additive effects, and VC is estimated if there is stronger evidence for common environmental effects. In extended-twin-family designs, VA, VD, VC and VE can be estimated simultaneously. Multivariate twin models can be used to model the cross -twin–cross-trait covariance, which is the covariance of trait one in one twin with trait two in the co -twin. The same principles apply to estimating the genetic and environmental influences on the clustering of different traits or com orbidity of disorders as for the expected covariances of twins. MZ twins share (nearly) 100% of their segregating genes, whereas DZ twins share on average 50% of their segregating genes. Twins of both types share 100% of the common environment and 0% of the unique environment. The value of twins in neuroimaging genetics Imaging genetics is a form of association analysis in which the phenotype is a measure of brain structure or function. Brain imaging studies in twins have shown that individual differences in brain structure and function are highly heritable. Two designs are commonly used in imaging genetics: Comparing disease-discordant and disease-concordant MZ twins to assess whether genetic and environmental risk factors for psychiatric disorders act on the same brain regions. Contrasting MZ twins who both score high on the disease phenotype to those who both score low to identify brain characteristi cs that are related to genetic risk for disease. Examples of imaging genetics studies A study of bipolar disorder found that white matter pathology in the frontal lobe may be central to the genetic risk of devel oping bipolar disorder, whereas widespread grey matter abnormalities may be more related to environmental effects and may reflect effects of the illness itself. A study of MZ twins who were discordant or concordant for anxious depression found that environmental risk is highlighted in the left temporal lobe. The study found that changes in the left parahippocampal area may be specific to an environmentally driven aetiology of anxiety and depression. Testing classical assumptions Genetic similarity of MZ twins: MZ twins are not genetically identical, but DNA sequence differences between MZ twins are not large. Genetic similarity of DZ twins: DZ twins share on average 50% of their segregating genes, but the true amount of genetic material that DZ twins have inheri ted from the same parent (identity-by-descent sharing (IBD sharing)) can vary from 42% to 58%. Environmental similarity of MZ and DZ twins: MZ twins may share environmental influences to a greater degree than DZ twins, because they are derived from a single zygote and may start out with more similar epigenomes. Implications for interpreting twin studies The heritability of phenotypes that are epigenetically regulated may be overestimated if MZ twins are epigenetically more sim ilar than DZ twins owing to non-genetic causes. Twin concordance and disease liability Relationship between heritability and discordance rates in MZ twins A high concordance of MZ twins does not necessarily imply a high heritability. A high rate of disease discordance in MZ twins does not rule out the importance of genetic influences. The probability of observing discordant MZ twins depends on the heritability of the underlying liability and on the level of the threshold. Trait concordance in MZ twins, penetrance and disease risk prediction The presence of disease-discordant twins indicates that genomes cannot completely predict the disease outcome of individuals, even if most variation in disease outcome between individuals is caused by genetic differences. For example, for schizophrenia, despite the high heritability of 80%, the probandwise concordance between MZ co -twins is only 40–50%. The fact that MZ twin concordance for common disorders is not always high has important implications for genomic risk predict ion and the ethical concerns that have been raised in this light. Even if we knew all of the genetic variants that contribute to differences in disease risk between individuals, we would stil l not be able to predict with certainty the disease risk of all individuals on the basis of their DNA sequence. Physical Similarity and the Equal-Environment Assumption in Twin Studies of Psychiatric Disorders (Hettema et al., 1995) (1) Introduction Traditional analysis of twin data and more recent structural equation models for twin analysis are predicated on the equal-environment assumption (EEA)---that monozygotic (MZ) and dizygotic (DZ) twins are equally correlated for their exposure to environmental influences that are of etiologic importance to the trait or disorder under study. The validity of the EEA is PSYC0036 Genes and Behaviour Page 1 Definitions Classical twin design The approach used to estimate the importance of genetic and environmental influences on complex trait variation. The estimate of heritability is based on a comparison of resemblance in monozygotic twins (who share all segregating genetic material) and dizygotic twins (who share, on average, half of their segregating genetic material). Heritability The proportion of variation in a trait that is due to heritable differences between individuals in a population: that is, the proportion of variation due to additive genetic effects (that is, narrow-sense heritability) or the proportion of variation due to all genetic effects (that is, broad-sense heritability). Discordant monozygotic twins (Discordant MZ twins). Twins who derive from a single fertilized egg cell but who are dissimilar for a certain characteristic or disease. By contrast, concordant MZ twins are phenotypically similar. Case–control study The comparison of individuals with a trait or disease of interest (cases) to controls to identify genes or other aspects associated with the trait. Cases and controls can be unrelated or can be relatives (withinfamily case –control design). Epigenome The entire collection of epigenetic marks, including DNA methylation and histone modifications, that regulate the expression of the genome. In contrast to the genome, the epigenome is specific to each cell. Zygosity assessment The assessment whether same-sex twins are monozygotic or dizygotic is often based on the comparison of DNA markers or alternatively on standardized questionnaires. Multivariate twin models Models used for the simultaneous analysis of multiple traits measured in monozygotic and dizygotic twins to estimate the importance of genetic and environmental influences shared (‘overlapping’) between traits in explaining their clustering, comorbidity or covariance. Additive Gene Action referred to as the phenomenon in which the two alleles of the gene contribute equally to the production of the phenotype. Non additive or dominance gene action refers to the phenomenon in which one allele is expressed stronger than the other allele Germline mosaicism a mutation that is limited to the gonads and can be transmitted to offspring Probandwise concordance a measure of the proportion of twins who have the illness who have an affected twin and can be calculated with the formula of 2C/(2C+D), in which C is the number of concordant pairs and D is the number of discordant pairs In other words, the probability that a co-twin of a person with a disease will also have the disease. dizygotic (DZ) twins are equally correlated for their exposure to environmental influences that are of etiologic importance to the trait or disorder under study. The validity of the EEA is crucial to these studies because, if incorrect, excess resemblance of MZ twins compared to DZ twins usually ascribed to genetic factors could be partly or entirely due to environmental factors. (2) Methods for testing the EEA There are five methods for testing the EEA: Direct observation of twins in a social situation: This method has found that excess resemblance in parental treatment of MZ compared to DZ twins was associated with parental behavior that was in response to twin behavior. Comparison of environmental similarity for MZ and DZ twins: This method has found no relationship between environmental similarity and twin resemblance for a variety of traits, including personality, intelligence, social attitudes, alcohol consumption, symptoms of anxiety and depression, clini cally diagnosed major depression, phobia, generalized anxiety disorder, and alcoholism. Obtaining parental reports of their treatment of their twin offspring: This method has found that similarity of parental treatment is unrelated to twin resemblance for cognitive abilities, personality, or vocational interests. Comparing the impact on twin resemblance of "real" versus "perceived" zygosity: This method has found little evidence that perceived zygosity influences twin resemblance. Examining the correlation between physical similarity of twin pairs and trait similarity: This method has not suggested that twin resemblance was substantially influenced by physical similarity. (3) New study assessing the impact of physical similarity on twin resemblance for five common psychiatric disorders This study has several advantages over most of the previous work: It is a large population-based sample. The diagnoses of the psychiatric disorders were made by an experienced clinician. The physical similarity of the twin pairs was assessed by direct ratings of adult twin photographs, which were compared to ch ildhood similarity measures reported by the twins and their parents. The results of this study will provide new information on the validity of the EEA and the role of environmental factors in th e etiology of psychiatric disorders Method Sample and Diagnostic Methods Sample: 1030 female twin pairs of known zygosity Diagnostic methods: ○ Modified Structured Clinical Interview for DSM-III-R (Spitzer et al., 1987) for major depression, generalized anxiety disorder, bulimia nervosa, and alcohol dependence ○ Adaptation of the Phobic Disorders section of the Diagnostic Interview Schedule (DIS) Version III-A (Robins and Helzer, 1985) for phobias Physical Similarity Rating 882 adult twin pairs were judged for similarity of appearance on a scale of 1 (most similar) to 7 (least similar) Seven measurement categories were collapsed into a dichotomous (most and least similar) and a trichotomous (most, moderately, and least similar) measurement scale for analysis purposes Intraclass correlation for the three raters = 0.98 Intraclass correlation for test-retest reliability = 0.97 Other ratings of physical similarity were determined by interview of the twins and their parents Method of Analysis Used a biometrical model that includes four latent sources of variation in liability to the diagnosed disorder (phenotype): ○ additive genetic effects (A), ○ specified common or familial environment (Cs), ○ residual common environment (CR), ○ individual specific environment € Violations of the EEA are attributable to the effects of the specified familial environment Cs, which in this study was index ed as the physical similarity of the twins Results The results of this study provide support for the EEA for all of the disorders studied except bulimia. For bulimia, the resul ts suggest that physical similarity may play a role in the etiology of the disorder, but this finding needs to be replicated in other studies Discussion Summary of the findings in the paper: Physical similarity rating of adult twin pairs by photograph was used as an index of specified common environment to test the validity of the EEA for twin studies of five psychiatric illnesses: major depression, generalized anxiety disorder, phobias, alcoholism, and bulimia. The results showed that for the four disorders of major depression, generalized anxiety disorder, phobias, and alcoholism, mo del fitting provided no evidence for a significant effect of physical similarity on twin resemblance for diagnosis. This is consistent with previous results obtained using perc eived zygosity as a form of specified common environment and further supports the validity of the EEA for twin studies of these disorders. However, the results for bulimia presented a different story. The findings indicated that for both broadly and narrowly defin ed bulimia, the best-fitting model is one that includes physical similarity as a significant factor, with the parameter estimate for Cs providing the largest contribution to the tot al variation in liability. These results suggest that there may be a violation of the EEA in twin studies for bulimia when one regards physical similari ty as a form of specified common environment. Limitations of the study: The high correlation between zygosity and physical similarity rating by photograph limited the ability to separate the effect s of these two variables. The lifetime prevalences for broadly and narrowly defined bulimia in this population were fairly low, which may have contribu ted to the instability of the results. Limiting the analysis to smaller samples may exclude specific twin pairs for which the effect of physical similarity is stron gest. A Test of the Equal-Environment Assumption In Twin Studies of Psychiatric Illness (Kendler et al., 1993) Introduction The traditional twin method and biometrical models for twin analysis rely on the EEA. EEA assumes that monozygotic (MZ) and dizygotic (DZ) twins share equal exposure to environmental influences relevant to the s tudied trait. If the EEA is incorrect, MZ twins' greater resemblance over DZ twins, typically attributed to genetics, might partly result f rom environmental effects. Methods for Testing the Validity of the EEA Method 1: Physical Similarity Resemblance in twins may be influenced by physical resemblance, reflecting the degree of physical similarity. Three studies tested this method but found no substantial influence of physical similarity on twin resemblance for traits lik e intelligence, personality, and schizophrenia. Method 2: Direct Observation in Family Settings This method involves observing twins in family settings, distinguishing self -initiated and response-driven behaviors. One study found that the excess parental treatment resemblance in MZ twins was entirely due to parental responses to twin beh avior. Method 3: Measurable Environmental Features Certain measurable features of childhood and adult environments are compared between MZ and DZ twins. Studies examined childhood factors like shared playmates, room -sharing, dressing alike, and adult factors like contact and cohabitation. No consistent relationship was found between childhood or adult environmental similarity and twin resemblance for various tra its like anxiety, depression, phobia, and alcoholism. Method 4: Perceived Zygosity This method compares trait similarity in twins based on both "real" zygosity assessed by investigators and "perceived" zygosi ty reported by twins or parents. It tests the influence of expectations on twin resemblance. Studies across traits like intelligence, attitudes, hyperactivity, and personality found little evidence that perceived zygos ity affects twin resemblance. Application to Psychiatric Disorders in Female-Female Twin Pairs This report introduces an assessment of the impact of perceived zygosity on twin resemblance for psychiatric disorders. The study uses personal structured psychiatric interviews in a large population -based sample of female-female twin pairs to explore this issue. Method Sample and Diagnostic Methods 2163 female twins from the population-based Virginia Twin Register were interviewed. Twins were diagnosed with major depression, generalized anxiety disorder, bulimia nervosa, alcohol dependence, and phobias us ing modified versions of the Structured Clinical Interview for DSM-III-R and the Diagnostic Interview Schedule. Zygosity Determination Zygosity was determined by reviewing information on physical similarity, frequency of confusion as children, and whether the twin and her cotwin were as alike as "two peas in a pod" or only of "normal family likeness." For twin pairs with uncertain zygosity, blood samples were obtained and DNA polymorphisms were examined. Final zygosity determination, which used blood samples where available and a definite or probable zygosity diagnosis otherwis e, yielded 590 MZ twin pairs, 440 DZ twin pairs, and 3 pairs classified as uncertain. Method of Analysis Specified familial environment ▪ A specified familial environment scale was created using self-report zygosity. ▪ Twins who both considered themselves to be identical were assigned a score of 1.0, pairs who both considered themselves to be fraternal a score of 0, and all other pairs a score of 0.50. Twin model ▪ A full twin model was fit to the data, including estimates of A (additive genetic effects), E (individual specific environment), Cs (specified common or family environment), and C~ (remaining or residual common environment). Results The results of the study suggest that the EEA assumption does not hold for the five psychiatric disorders considered in the s tudy. the study found that the similarity of twins in their self -report zygosity did not have a significant impact on their similarity in liability to the disorders. This suggests that the environment is likely to play a more important role in the development of these disorders than previou sly thought Discussion Zygosity Agreement in Female-Female Twin Pairs In a population-based sample of female-female adult twin pairs: ○ Self-reported zygosity agreed with assigned zygosity in about 85% of pairs. ○ This rate is somewhat higher than in previous reports involving younger twins and parental input. Accuracy of Self-Reported Zygosity Adult twins may be more accurate in assessing their own zygosity than younger twins or their parents. Disagreements between self-reported and assigned zygosity were not symmetrical. More MZ twins considered themselves to be DZ than vice versa. Reasons for Mistaken Zygosity Beliefs in MZ Twins MZ twins who believed they were DZ were less likely to base their opinion on physical appearance. They were more likely to base their opinion on what their parents were told at their birth. Suggests that the asymmetry in mistaken zygosity beliefs may arise from mothers of dichorionic MZ twins being mistakenly told at birth that their children were DZ. Impact of Perceived Zygosity on Twin Resemblance for Psychiatric Disorders Structural equation modelling was applied to five major psychiatric disorders in the sample. Estimated the impact of "self-report" zygosity as a form of specified common environment. Results showed no significant effect of perceived zygosity on twin resemblance for any of the five disorders. Suggests that social and personal expectations associated with being identical or fraternal twins have little effect on twin resemblance for psychiatric disorders. Additional Considerations Results should be interpreted considering two methodologic limitations: ○ Relatively small number of twins with disagreed perceived and assigned zygosity. ○ Limited number of zygosity diagnoses made using blood-group or DNA polymorphisms. PSYC0036 Genes and Behaviour Page 2