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BMC Medical Genomics May 2015Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial...
BACKGROUND
Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial disease with a discordance rate of ~50% in monozygotic twins. This high discordance is often explained by the role of yet unknown environmental, random, and epigenetic factors. The involvement of DNA methylation in this disease appears logical, but remains to be established.
METHODS
We have used blood DNA from two pairs of monozygotic twins discordant for schizophrenia and their parents in order to assess genome-wide methylation using a NimbleGen Methylation Promoter Microarray.
RESULTS
The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins. Some DMRs are shared with parent(s) and others appear to be de novo. We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families. Interestingly, the genes affected by pair specific DMRs share specific networks. Specifically, this study has identified two networks; "cell death and survival" and a "cellular movement and immune cell trafficking". These two networks and the genes affected have been previously implicated in the aetiology of schizophrenia.
CONCLUSIONS
The results are compatible with the suggestion that DNA methylation may contribute to the discordance of monozygotic twins for schizophrenia. Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes. It supports the extensive genetic, epigenetic and phenotypic heterogeneity implicated in schizophrenia.
Topics: Adult; CpG Islands; DNA Methylation; Diseases in Twins; Epigenesis, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Genome, Human; Histones; Humans; Middle Aged; Multigene Family; Pedigree; Phenotype; Promoter Regions, Genetic; Psychotic Disorders; Schizophrenia; Twins, Monozygotic
PubMed: 25943100
DOI: 10.1186/s12920-015-0093-1 -
PloS One 2015Monozygotic twins share identical genomic DNA and are indistinguishable using conventional genetic markers. Increasing evidence indicates that monozygotic twins are...
Monozygotic twins share identical genomic DNA and are indistinguishable using conventional genetic markers. Increasing evidence indicates that monozygotic twins are epigenetically distinct, suggesting that a comparison between DNA methylation patterns might be useful to approach this forensic problem. However, the extent of epigenetic discordance between healthy adult monozygotic twins and the stability of CpG loci within the same individual over a short time span at the whole-genome scale are not well understood. Here, we used Infinium HumanMethylation450 Beadchips to compare DNA methylation profiles using blood collected from 10 pairs of monozygotic twins and 8 individuals sampled at 0, 3, 6, and 9 months. Using an effective and unbiased method for calling differentially methylated (DM) CpG sites, we showed that 0.087%-1.530% of the CpG sites exhibit differential methylation in monozygotic twin pairs. We further demonstrated that, on whole-genome level, there has been no significant epigenetic drift within the same individuals for up to 9 months, including one monozygotic twin pair. However, we did identify a subset of CpG sites that vary in DNA methylation over the 9-month period. The magnitude of the intra-pair or longitudinal methylation discordance of the CpG sites inside the CpG islands is greater than those outside the CpG islands. The CpG sites located on shores appear to be more suitable for distinguishing between MZ twins.
Topics: Adult; Aged; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Forensic Genetics; Genetic Markers; Genome, Human; Humans; Male; Middle Aged; Multigene Family; Promoter Regions, Genetic; Reproducibility of Results; Twins, Monozygotic
PubMed: 26248206
DOI: 10.1371/journal.pone.0135022 -
Translational Psychiatry Sep 2019DNA methylation plays an important role in major depressive disorder (MDD), but the specific genes and genomic regions associated with MDD remain largely unknown. Here...
DNA methylation plays an important role in major depressive disorder (MDD), but the specific genes and genomic regions associated with MDD remain largely unknown. Here we conducted genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) and gene expression (RNA-seq) in peripheral blood monocytes from 79 monozygotic twin pairs (mean age 38.2 ± 15.6 years) discordant on lifetime history of MDD to identify differentially methylated regions (DMRs) and differentially expressed genes (DEGs) associated with MDD, followed by replication in brain tissue samples. Integrative DNA methylome and transcriptome analysis and network analysis was performed to identify potential functional epigenetic determinants for MDD. We identified 39 DMRs and 30 DEGs associated with lifetime history of MDD. Some genes were replicated in postmortem brain tissue. Integrative DNA methylome and transcriptome analysis revealed both negative and positive correlations between DNA methylation and gene expression, but the correlation pattern varies greatly by genomic locations. Network analysis revealed distinct gene modules enriched in signaling pathways related to stress responses, neuron apoptosis, insulin receptor signaling, mTOR signaling, and nerve growth factor receptor signaling, suggesting potential functional relevance to MDD. These results demonstrated that altered DNA methylation and gene expression in peripheral blood monocytes are associated with MDD. Our results highlight the utility of using peripheral blood epigenetic markers and demonstrate that a monozygotic discordant co-twin control design can aid in the discovery of novel genes associated with MDD. If validated, the newly identified genes may serve as novel biomarkers or druggable targets for MDD and related disorders.
Topics: Adult; DNA Methylation; Depressive Disorder, Major; Diseases in Twins; Epigenome; Female; Gene Expression Profiling; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Transcriptome; Twins, Monozygotic; Young Adult
PubMed: 31477685
DOI: 10.1038/s41398-019-0550-2 -
Omics : a Journal of Integrative Biology Mar 2008Differences in genetic background and/or environmental exposure among individuals are expected to give rise to differences in measurable characteristics, or phenotypes....
Differences in genetic background and/or environmental exposure among individuals are expected to give rise to differences in measurable characteristics, or phenotypes. Consequently, genetic resemblance and similarities in environment should manifest as similarities in phenotypes. The metabolome reflects many of the system properties, and is therefore an important part of the phenotype. Nevertheless, it has not yet been examined to what extent individuals sharing part of their genome and/or environment indeed have similar metabolomes. Here we present the results of hierarchical clustering of blood plasma lipid profile data obtained by liquid chromatography-mass spectrometry from 23 healthy, 18-year-old twin pairs, of which 21 pairs were monozygotic, and 8 of their siblings. For 13 monozygotic twin pairs, within-pair similarities in relative concentrations of the detected lipids were indeed larger than the similarities with any other study participant. We demonstrate such high coclustering to be unexpected on basis of chance. The similarities between dizygotic twins and between nontwin siblings, as well as between nonfamilial participants, were less pronounced. In a number of twin pairs, within-pair dissimilarity of lipid profiles positively correlated with increased blood plasma concentrations of C-reactive protein in one twin. In conclusion, this study demonstrates that in healthy individuals, the individual genetic background contributes to the blood plasma lipid profile. Furthermore, lipid profiling may prove useful in monitoring health status, for example, in the context of personalized medicine.
Topics: Adolescent; C-Reactive Protein; Chromatography, Liquid; Female; Humans; Lipids; Male; Spectrometry, Mass, Electrospray Ionization; Twins, Monozygotic
PubMed: 18266560
DOI: 10.1089/omi.2007.0048 -
Journal of the American Academy of... Dec 2018Callous-unemotional (CU) traits increase risk for children to develop severe childhood aggression and conduct disorder. CU traits are typically described as highly...
OBJECTIVE
Callous-unemotional (CU) traits increase risk for children to develop severe childhood aggression and conduct disorder. CU traits are typically described as highly heritable, and debate continues about whether the parenting environment matters in their etiology. Strong genetically informed designs are needed to test for the presence of environmental links between parenting practices and CU traits. Our objective was to determine whether parental harshness and parental warmth were related to children's aggression or CU traits when accounting for genetically mediated effects.
METHOD
We examined 227 monozygotic twin pairs (454 children) drawn from population-based and at-risk samples of twin families, leading to oversampling of twins living in poverty. We computed multi-informant difference scores combining mother and father reports of their harshness and warmth toward each twin, and differences in mother reports of each twin's aggression and CU traits.
RESULTS
Twin differences in parental harshness were related to differences in both aggression and CU traits, such that the twin who received harsher parenting had higher aggression and more CU traits. Differences in parental warmth were uniquely related to differences in CU traits, such that the twin receiving warmer parenting evidenced lower CU traits. These effects were not moderated by child sex, age, or family income, with the exception that the relationship between differential parental harshness and differential child aggression was stronger among low-income families.
CONCLUSION
Parenting is related to child CU traits and aggression, over and above genetically mediated effects, with low parental warmth being a unique environmental correlate of CU traits.
Topics: Aggression; Child; Conduct Disorder; Emotions; Environment; Female; Humans; Male; Parent-Child Relations; Parenting; Poverty; Twins, Monozygotic
PubMed: 30522741
DOI: 10.1016/j.jaac.2018.07.882 -
Journal of Abnormal Child Psychology Jun 2019Community violence exposure and harsh parenting have been linked to maladaptive outcomes, possibly via their effects on social cognition. The Social Information...
Community violence exposure and harsh parenting have been linked to maladaptive outcomes, possibly via their effects on social cognition. The Social Information Processing (SIP) model has been used to study distinct socio-cognitive processes, demonstrating links between community violence exposure, harsh parenting, and maladaptive SIP. Though much of this research assumes these associations are causal, genetic confounds have made this assumption difficult to rigorously test. Comparisons of discordant monozygotic (MZ) twins provide one empirical test of possible causality, as differences between MZ twins must be environmental in origin. The present study examined effects of parenting and community violence exposure on SIP - specifically aggressive and avoidant social goals - in a sample of 426 MZ twin dyads (N = 852 twins, 48% female). Phenotypically, we found that lower positive parenting and greater harsh parenting were associated with greater endorsement of dominance and revenge goals. We also found that indirect and direct community violence exposure was associated with greater endorsement of avoidance goals. Using an MZ difference design, we found that the relationships between lower levels of positive parenting and endorsement of dominance and revenge goals were due, in part, to environmental processes. Moreover, the relationships between the impact of indirect and direct community violence exposure and avoidance goals, as well as between the impact of indirect community violence exposure and revenge goals, appeared to be due to non-shared environmental processes. Our results establish social and contextual experiences as important environmental influences on children's social goals, which may increase risk for later psychopathology.
Topics: Aggression; Child; Exposure to Violence; Female; Goals; Humans; Male; Parent-Child Relations; Parenting; Residence Characteristics; Social Behavior; Twins, Monozygotic
PubMed: 30604154
DOI: 10.1007/s10802-018-0506-7 -
JAMA Psychiatry Jul 2023General and specific factors of psychopathology are associated with future adverse outcomes, indicating that they might be useful for identifying individuals at greatest...
IMPORTANCE
General and specific factors of psychopathology are associated with future adverse outcomes, indicating that they might be useful for identifying individuals at greatest risk. However, it remains unknown if these associations are attributable to confounders that may influence both the psychopathology factors and later outcomes.
OBJECTIVE
To analyze associations between psychopathology factors and clinically relevant outcomes within family pairs, adjusting for unmeasured confounds by applying co-twin control and sibling comparison designs.
DESIGN, SETTING, AND PARTICIPANTS
This longitudinal cohort study with a follow-up range of 9 to 13 years included all Swedish twins born from 1959 to 1985 who participated in the Study of Twin Adults: Genes and Environment (60% response rate) and the oldest pair of all Swedish siblings born from 1959 to 1985 per the Multi-Generation Register. Twins were evaluated based on responses to a hierarchical factor model derived using multivariate statistics. Sibling pairs were evaluated based on psychiatric diagnoses per the Swedish National Patient Register. Information on outcome events and prescriptions were derived from the National Patient Register, Prescribed Drug Register, and Crime Register. Baseline assessment was in August 2005, and data were analyzed from January 2022 to February 2023.
EXPOSURES
Hierarchical factor model consisting of 1 general and 4 specific factors fit to 48 psychiatric symptoms on which twin participants self-reported in 2005 and 1 general and 3 specific factors fit to 9 register-based psychiatric diagnoses assigned to sibling participants prior to 2005.
MAIN OUTCOMES AND MEASURES
Outcomes consisted of 7 register-based events occurring after 2005, including suicidal behavior, substance overdoses, and criminal suspicion or convictions (data available until the end of 2013), and prescription of antidepressants, antialcohol or antiopioid medication, antipsychotics, and stimulants (data available until the end of 2017).
RESULTS
The study included 32 328 twins (mean [SD] age, 34 [8] years; 16 076 [49.73%] male) and 1 942 106 siblings (mean [SD] age, 34 [7] years; 991 500 [51.05%] male). General psychopathology was significantly associated with all 7 outcomes within sibling pairs (mean within-pair odds ratio [OR], 2.28; 95% CI, 2.19-2.37) and dizygotic twin pairs (within-pairs OR, 1.65; 95% CI, 1.38-1.98) and with 3 outcomes within monozygotic twin pairs (mean within-pairs OR, 1.77; 95% CI, 1.35-2.36). Within sibling pairs, the specific internalizing factor was associated with antidepressant prescriptions (within-pairs OR, 1.65; 95% CI, 1.59-1.71), the specific substance misuse factor was associated prescription of antialcohol and antiopioid medication (within-pairs OR, 2.36; 95% CI, 2.20-2.54), and the specific psychotic factor was associated with antipsychotic medications (within-pairs OR, 1.61; 95% CI, 1.51-1.72). Similar results emerged within twin pairs.
CONCLUSION AND RELEVANCE
In this cohort study, general psychopathology was significantly associated with all 7 outcomes within sibling and dizygotic twin pairs and 3 outcomes within monozygotic twin pairs at 10 years. Within twin and sibling pairs, the specific factors were primarily associated with related outcomes. Several of the associations in this cohort study could not be attributed to unmeasured confounds shared by family members, suggesting that interventions toward broad psychopathology dimensions might help reduce the risk of future clinically relevant events.
Topics: Humans; Adult; Male; Female; Siblings; Longitudinal Studies; Sweden; Twins, Monozygotic; Mental Disorders; Twins, Dizygotic; Registries
PubMed: 37163290
DOI: 10.1001/jamapsychiatry.2023.1162 -
Journal of Child Psychology and... Jan 2021Whereas short and problematic sleep are associated with psychological problems in adolescence, causality remains to be elucidated. This study therefore utilized the...
BACKGROUND
Whereas short and problematic sleep are associated with psychological problems in adolescence, causality remains to be elucidated. This study therefore utilized the discordant monozygotic cotwin design and cross-lagged models to investigate how short and problematic sleep affect psychological functioning.
METHODS
Adolescent twins (N = 12,803, 13-20 years, 42% male) completed questionnaires on sleep and psychological functioning repeatedly over a two-year interval. Monozygotic twin pairs were classified as concordant or discordant for sleep duration and trouble sleeping. Resulting subgroups were compared regarding internalizing problems, externalizing problems, and subjective well-being.
RESULTS
Cross-sectional analyses indicated associations of worse psychological functioning with both short sleep and problematic sleep, and cross-lagged models indicate bidirectional associations. Longitudinal analyses showed that an increase in sleep problems experienced selectively by one individual of an identical twin pair was accompanied by an increase of 52% in internalizing problem scores and 25% in externalizing problem scores. These changes were significantly different from the within-subject changes in cotwins with unchanged sleep quality (respectively, 3% increase and 5% decrease). Psychological functioning did, however, not worsen with decreasing sleep duration.
CONCLUSIONS
The findings suggest that sleep quality, rather than sleep duration, should be the primary target for prevention and intervention, with possible effect on psychological functioning in adolescents.
Topics: Adolescent; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Humans; Longitudinal Studies; Male; Sleep; Twins, Monozygotic
PubMed: 32396669
DOI: 10.1111/jcpp.13238 -
Neuropsychologia Jun 2023Reared-apart twin studies are a powerful means for identifying the relative contributions of heredity and environment to variation in human physical and behavioural... (Review)
Review
Reared-apart twin studies are a powerful means for identifying the relative contributions of heredity and environment to variation in human physical and behavioural traits. One such characteristic is handedness, for which it has long been noted that approximately 20% of twin pairs are comprised of one right-handed cotwin and one left-handed cotwin. Reared-together twin studies suggest a slightly greater concordance in monozygotic (MZT) than dizygotic (DZT) twins, implying that genetics influences hand preference. We report here two studies of handedness in reared-apart twins. Study 1 synthesizes the available data and estimates that at least N = 560 same-sex reared-apart twin pairs (for which zygosity is known with reasonable confidence) have been identified. Of these, handedness data are available for both members of n = 415 pairs. We observed similar levels of concordance/discordance for reared-apart monozygotic (MZA) and dizygotic (DZA) twins. However, although direction of handedness (right or left) has frequently been examined, strength of handedness (strong or weak) has not. Study 2 examined strength of hand preference and relative hand skill, as well as right- and left-hand speed, information available for participants in the Minnesota Study of Twins Reared Apart (MISTRA). We provide evidence of heritability for right-hand and left-hand speed. We also found hand preference strength was more alike than chance in DZA, but not MZA, twins. Findings are discussed in relation to genetic and environmental influences on human handedness.
Topics: Humans; Twins, Monozygotic; Functional Laterality; Twins, Dizygotic; Mental Processes
PubMed: 37059260
DOI: 10.1016/j.neuropsychologia.2023.108523 -
Paediatric and Perinatal Epidemiology Jan 2005Evidence has accumulated that low birthweight is associated with several risk factors for cardiovascular disease. However, it is not known whether or not these... (Review)
Review
Intrauterine environmental and genetic influences on the association between birthweight and cardiovascular risk factors: studies in twins as a means of testing the fetal origins hypothesis.
Evidence has accumulated that low birthweight is associated with several risk factors for cardiovascular disease. However, it is not known whether or not these associations are due to a programmed response to intrauterine malnutrition or genetic factors influencing both birthweight and cardiovascular risk factors. Twin studies offer a unique opportunity to distinguish between intrauterine and genetic origins of the association between birthweight and cardiovascular risk. In our twin cohort, low birthweight was associated with insulin resistance, lower HDL and shorter height within both dizygotic and monozygotic twin pairs, suggesting that these associations are, at least in part, independent of genetic factors. In contrast, low birthweight was associated with blood pressure, total and LDL cholesterol, fibrinogen and sympathetic activation within dizygotic twin pairs, but not within monozygotic twin pairs. These differences between dizygotic and monozygotic twins suggest that these associations are, at least in part, due to genetic factors. Therefore, both intrauterine environmental and genetic factors appear to play a role in the association between birthweight and cardiovascular risk factors. In the future, strategies may be developed targeted at improving or preventing impaired intrauterine growth. However, the effects of interventions that comprise changes in environment within the normal range may be limited due to the possible important role of genetic factors.
Topics: Adolescent; Adult; Cardiovascular Diseases; Female; Fetal Nutrition Disorders; Humans; Infant, Low Birth Weight; Infant, Newborn; Pregnancy; Pregnancy, Multiple; Prenatal Exposure Delayed Effects; Risk Factors; Twin Studies as Topic; Twins, Dizygotic; Twins, Monozygotic
PubMed: 15670116
DOI: 10.1111/j.1365-3016.2005.00614.x