Search

Gilles de la Tourette Syndrome (GTS) is a multifactorial neurodevelopmental disorder characterized by tics and multiple comorbidities. The pathophysiology is not yet fully understood, but both environmental and genetic risk factors seem to be involved. Twin studies provide important knowledge on genetic factors. We assessed the concordance of GTS and chronic tic disorders (CTD) in monozygotic (MZ) twins, and examined tic severity, symptoms of obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder and autism spectrum disorder. Twin pairs, where at least one twin was diagnosed with any tic disorder, were identified through Danish Twin Registry, Psychiatric Central Registry, Danish National Patient Registry and National Tourette Clinic, Copenhagen University Hospital, Herlev. Zygosity was tested with single-nucleotide polymorphism (SNP) genotyping and clinical assessment was done with validated tools. 14 MZ twin pairs were included: five were discordant. Seven twin pairs were concordant for GTS, and for two pairs one twin had GTS and the other CTD. Among the twins with CTD or GTS, 50% had at least one comorbidity, which is higher than in background populations. The GTS + OCD-phenotype was significantly more frequent among GTS-concordant than among discordant twins. No statistically significant differences were found between the GTS-concordant and discordant twin pairs regarding tic severity or comorbidities. Thorough clinical assessment and SNP-based genotyping are important when conducting clinical twin studies. We found high concordance of GTS and CTD, which supports the notion that both disorders have common genetic risk factors. Further studies with larger cohorts including dizygotic twins are warranted for more conclusive results.

Background/aims Research linking orbitofrontal cortex (OFC) structure and substance use disorders (SUDs) is largely correlational and often implies a causal effect of addiction/substance exposure on the brain, but familial risk factors (e.g. genetic liability) may confound these associations. We tested whether associations between alcohol, cannabis and tobacco use disorders and OFC thickness reflected the potential causal effects of familial risk or SUDs-related consequences (e.g. substance exposure). Design A co-twin control/discordant twin design separated familial risk confounding from SUD-related consequences. Setting/participants A population-based sample of 436 24-year-old twins (62% monozygotic) from the Minnesota Twin Family Study, USA. Measurements Alcohol, cannabis and tobacco use disorders were assessed using the Composite International Diagnostic Interview-Substance Abuse Module. Cortical thickness of the medial and lateral OFC (mOFC and lOFC, respectively) was assessed using magnetic resonance imaging (MRI). Findings Lower mOFC (P-values ≤ 0.006) but not lOFC (P-values ≥ 0.190) thickness was observed in diagnosed individuals (n = 185) relative to non-SUD controls (n = 251). Co-twin control analyses offered evidence that mOFC associations were consistent with familial risk across SUDs (between-pair effect: P-values ≤ 0.047) and the independent consequences of having an alcohol or cannabis use disorder (within-pair effect: P-values ≤ 0.024). That is, within alcohol/cannabis discordant twin pairs, affected twins had significantly lower mOFC thickness compared with their unaffected co-twins. Conclusions A confounder-adjusted analysis of the Minnesota Twin Family Study appeared to indicate that, beyond a substance use disorders general familial risk effect, the experience of an alcohol or cannabis use disorder in emerging adulthood reduces the thickness of the medial orbitofrontal cortex, a region associated with value-guided decision-making.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease, which leads to neurodegenerative processes that cause neuron demyelination. MS is multifactorial with uncertain etiology, where interactions between genetic makeup of an individual and environmental factors influence disease risk. More than 200 risk variants have been implicated in MS, each contributed to understanding the etiology of MS through providing meaningful clues of the functional mechanisms underlying the development of this disease. This study aimed to identify genetic variants associated with MS in the Jordanian population. We performed whole exome sequencing for eight pairs of related patients from eight different families including one pair of discordant monozygotic twins, to determine the shared genetic information and genetic variants, and their correlation to MS. We identified rare exonic missense and frame shift variants segregating in all patients in MUC6, MUC16, and MUC19 genes, which are involved in innate immunity, in addition to ZNF717 gene. Moreover, variants in two of the previously described MS genes (HLA-DRB1, HLA- DRQ1) were also segregating in most patients. These molecular genetic details require further validation and functional analysis, to be implicated in the clinical diagnosis process of MS. This is the first attempt to characterize the genetic factors associated with MS in the Jordanian population.

The present study used a longitudinal and discordant twin design to explore in depth the developmental associations between victimization and loneliness from mid-childhood to young adulthood. The data were drawn from the Environmental Risk (E-Risk) Longitudinal Twin Study, a birth cohort of 2,232 individuals born in England and Wales during 1994–1995. Diverse forms of victimization were considered, differing across context, perpetrator, and timing of exposure. The results indicated that exposure to different forms of victimization was associated with loneliness in a dose–response manner. In childhood, bullying victimization was uniquely associated with loneliness, over and above concurrent psychopathology, social isolation, and genetic risk. Moreover, childhood bullying victimization continued to predict loneliness in young adulthood, even in the absence of ongoing victimization. Within-twin pair analyses further indicated that this longitudinal association was explained by genetic confounds. In adolescence, varied forms of victimization were correlated with young adult loneliness, with maltreatment, neglect, and cybervictimization remaining robust to controls for genetic confounds. These findings indicate that vulnerability to loneliness in victimized young people varies according to the specific form of victimization in question, and also to the developmental period in which it was experienced.

BackgroundA variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited.MethodsUsing well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD.ResultsRNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control.ConclusionsThe convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.

Marriage and parenthood are associated with alcohol use and use disorder (AUD), although they are confounded such that many studies struggle to identify their unique and/or causal effects. The present study utilized a genetically-informed discordant twin design that strengthens the putative causal role of marital and parental status in the presentation of AUD symptoms by using each individual’s co-twin as their own control while simultaneously modeling both predictors among men and women. Participants were 980 complete same-sex twin pairs from the Australian Twin Registry (M(age)=31.70 [SD=2.48]; 71% women). Marital status, parental status, and past year AUD symptoms were assessed via semi-structured interview. Three random-intercept generalized linear mixed models were fit in men and women including 1) marital status only, 2) parental status only, and 3) both marital and parental status; demographics, past year pregnancy, age of first drink, age of regular drinking, personality traits, and antisociality were included as covariates. Models tested for quasi-causal and familial effects. The sole-predictor marital status model (model 1) provided the best fit among men, while the simultaneous-predictor marital and parental status model (model 3) provided the best fit among women. Sole-predictor models showed familial effects of both predictors among men, and quasi-causal and familial effects of both predictors among women; the simultaneous-predictor model revealed familial effects of marital status only among men, and quasi-causal effects of parental status only among women. The present study elucidates important sex differences in the presentation of AUD among midlife adults in the context of notable developmental milestones.

Understanding the mechanisms behind aggressive behavior (AGG) is vital so that effective prevention and intervention strategies can be developed. Maltreated children are hypothesized to be prone to social information processing biases, such as hostile attribution bias (HAB), which, in turn, may increase the likelihood of behaving aggressively. The first aim of the present study was to replicate findings regarding associations between childhood maltreatment (CM), HAB, and aggression in a population‐based sample of Finnish female twins and their sisters (N = 2,167). However, these associations might not be causal but instead confounded by familial factors, shared between the variables. The second aim was, thus, to test the associations when potential confounding by familial (genetic or common environmental) effects were controlled for using a multilevel discordant twin and sibling design within (a) 379 pairs of twins (n pairs = 239) or siblings (n pairs = 140), and (b) within the 131 monozygotic (MZ) twin pairs. Consistent with previous studies, HAB mediated the association between CM and AGG when familial confounding was uncontrolled. No support was found for the mediation when controlling for familial confounding. Between‐pair associations were found between CM and AGG, and between CM and HAB. In addition, within‐pair associations were found between HAB and AGG, and between CM and AGG, however, these were nonsignificant in the discordant MZ analysis, offering the most stringent control of familial confounding. The results indicate the necessity of taking familial confounding into account when investigating the development of AGG.

BackgroundDespite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG.MethodsParticipants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates.ResultsNeither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality.ConclusionsThese findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.

Background Twin growth discordance was demonstrated to be a risk factor for adverse perinatal outcomes, and prenatal ultrasonographic methods were utilized to predict twin growth discordance to improve outcomes. The results currently reported are not consistent due to the poor unified parameters and gestational durations. Methods A total of 71 dichorionic twins with growth discordance and 346 dichorionic twins with normal growth were respectively included in the retrospective cohort study. The weight discordance of more than 25% was defined as a “growth discordant twin”. The clinical baseline information, maternal outcomes, twin birth weights and fetal growth parameters (which were measured by ultrasound) were compared between the two groups from early gestation to late gestation. Multiple logistic regression and receiver operating characteristic curves were adopted to evaluate the predictive value of the growth parameters. Results Compared with normal dichorionic twins, the clinical baseline conditions were similar in the twins those finally developed growth discordance. The fetal growth parameters and the deepest volume pocket of amniotic fluid in early and mid-pregnancy showed no obvious predictive values. The fetal growth parameters in late pregnancy showed predictive values, especially the discordance of estimated fetal weight (EFW) in the early third-trimester (P Conclusion Two assessment approaches were suggested and adopted to predict twin growth discordance in the current study. Twin growth should be assessed longitudinally and dynamically. Normal twins may show growth imbalance in the early stage. The discordance of EFW in late pregnancy may be a useful indicator for a growth discordance of more than 25%, which is required further confirmation.

Background As common risk factors of dementia, nine factors (low education, hearing loss, obesity, hypertension, smoking, depression, physical inactivity, diabetes and social isolation) were proposed. However, the joint impact of these factors on incident dementia is still uncertain; hence, we aimed to examine this impact. Methods We conducted a cohort study of 9017 cognitively intact individuals aged ≥ 65 years in the Swedish Twin Registry. The main exposure was the total number of reported risk factors (ranging from 0 to 9). Data on dementia diagnoses were based on clinical workup and national health registers. After estimating the adjusted hazard ratios of incident dementia, the population attributable fraction (PAF) was calculated. We then conducted additional analyses, including APOE e4 status in a genotyped subsample (n = 2810) to check the relative impact of the main exposure and discordant twin pair (n = 1158) analysis to consider confounding by familial effects (shared genetic or familial environmental factors). Results The number of dementia cases was 1950 (21.6%). A dose-response relationship between the number of risk factors and incident dementia was observed; hazard ratio (95% confidence interval) per one-unit increment in number of risk factors was 1.07 (1.03 to 1.11). The PAF for the combination of the nine risk factors was 10.4%. The PAF of all nine risk factors was smaller than that of APOE e4 genotype (20.8%) in the subsample. Discordant pair analysis suggested that the observed association was not likely explained by familial effects. Conclusion The nine risk factors may have considerable impact as modifiable factors on incident dementia.

Magnetic resonance imaging (MRI) studies have identified neural structures implicated in the pathophysiology of mood disorders, especially bipolar disorder (BD) and major depressive disorder (MDD). However, the role of genetic and environmental influences on such brain deficits is still unclear. In this context, the present review summarizes the current evidence from structural MRI and Diffusion Tensor Imaging (DTI) studies on twin samples concordant or discordant for BD or MDD, with the aim of clarifying the role of genetic and environmental risk factors on brain alterations. Although the results showed a complex interplay between gene and environment in affective disorders, the evidence seem to underline that both genetic and environmental risk factors have an impact on brain areas and vulnerability to MDD and BD. However, the precise mechanism of action and the interaction between these factors still needs to be unveiled. Therefore, future larger studies on concordant or discordant twins should be encouraged, because this population provides a unique opportunity to probe separately genetic and environmental markers of disease vulnerability.

Genetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.

Aims To investigate how strongly smoking dependence and smoking dependence motives are associated with depressive symptoms among daily smokers and if these associations are independent of measured confounders and shared familial factors. Design Cross-sectional individual-based and within-pair analyses. Setting Fourth wave of the population-based Finnish Twin Cohort conducted in 2011. Participants 918 daily smokers born 1945-1957 (48% men), mean age 59.5 years including 38 twin pairs discordant for depression. Measurements Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale with a cut off value >= 20 for depression. Smoking dependence was assessed using the Fagerstrom Test for Cigarette Dependence (FTCD) and smoking dependence motives with three subscales from the multi-dimensional Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM): primary dependence motives (PDM), affective enhancement (AE), and Taste. Logistic regressions, using standardized scores of independent variables and adjusted for multiple confounders with correction for sampling as twin pairs, were used in the individual-based analyses. Conditional logistic regression was used to control for shared familial factors in discordant twin pairs. Findings Prevalence of depression was 18% (n = 163: 61 [14%] in men, n = 102 [22%] in women). Higher smoking dependence measured by the FTCD (OR 1.45; 95% CI 1.20, 1.75), and dependence motives measured by the PDM (1.56; 1.30, 1.87) and the AE (1.54; 1.28, 1.85) were associated with higher odds of depression. The associations remained after adjusting for individual confounders, except for neuroticism, which attenuated all associations. FTCD, PDM, and AE showed associations with depression within depression-discordant monozygotic pairs, suggesting an association independent of familial factors. Conclusions Depression appears to be associated with smoking dependence and smoking dependence motives related to heavy, automatic use and use to regulate affective states. The associations appear to be confounded or mediated by neuroticism but are independent of shared familial influences.

The aim of this study was to investigate the expression features of discordant inflammatory bowel disease (IBD) twin pairs to identify novel molecular features and markers. We collected an expression dataset of discordant twin pairs with ulcerative colitis and performed integrative analysis to identify the genetic-independent expression features. Through deconvolution of the immune cell populations and tissue expression specificity, we refined the candidate genes for susceptibility to ulcerative colitis. We found that dysregulated immune systems and NOD-related pathways were enriched in the expression network of the discordant IBD twin pairs. Among the identified factors were significantly increased proportions of immune cells, including megakaryocytes, neutrophils, natural killer T cells, and lymphatic endothelial cells. The differentially expressed genes were significantly enriched in a gene set associated with cortical and medullary thymocytes. Finally, by combining these expression features with genetic resources, we identified some candidate genes with potential to serve as novel markers of ulcerative colitis, such as CYP2C18. Ulcerative colitis is a subtype of inflammatory bowel disease and a polygenic disorder. Through integrative analysis, we identified some genes, such as CYP2C18, that are involved in the pathogenesis of IBD as well as some candidate therapeutic targets, such as LOXL2.

Differences in concordance rates between monozygotic and dizygotic twin pairs with Parkinson's disease (PD) have been used to estimate genetic influences in PD pathogenesis. We hypothesized that “discordance” may not in all cases adequately reflect the multifaceted disease manifestation of PD that involves a continuum from prodromal to definite PD. Deep clinical phenotyping, combining motor, nonmotor, and imaging modalities in five monozygotic, seemingly discordant twin pairs revealed motor and/or nonmotor features and/or nigral hyperechogenicity in all of the five putatively unaffected twins. In conclusion, our data suggest that concordance rates in monozygotic twins may be higher than previously appreciated.

The quality of the neighborhood in which one lives has been linked to disordered gambling (DG), but whether this reflects a causal relation has not yet been empirically examined. Participants were 3,450 Australian twins who completed assessments of past-year DG and personality and for whom census-derived indicators of disadvantage were used to characterize their neighborhood. Multilevel models were employed to estimate within-twin-pair and between-twin-pair effects of neighborhood disadvantage on DG, with the within-twin-pair effect representing a potentially causal association and the between-twin-pair effect representing a noncausal association. There was robust evidence for a potentially causal (as well as a noncausal) effect of neighborhood disadvantage on DG; in contrast, parallel analyses of past-year alcohol-use disorder (AUD) failed to find evidence of a potentially causal effect. These results support efforts focused on identifying the active ingredients contributing to the effect of neighborhood disadvantage on DG and developing interventions to limit their impact.

Low mitochondrial DNA copy number (mtDNA CN) has been associated with e.g. cancer, cardiovascular and autoimmune diseases. We aimed to study a potential association between mtDNA CN and rheumatoid arthritis (RA). The relative quantity of mitochondrial DNA compared to nuclear DNA was measured in peripheral white blood cells from 149 RA affected twin pairs and 1321 non-affected twin pairs. Multiple regression analysis including RA discordant twin pairs was performed in order to separate specific effects of RA and familial RA predisposition using non-RA affected twin pairs as reference group. In addition, we performed a twin pair level analysis including only RA discordant twin pairs evaluating the effect of cell type, auto antibodies and RA genetic risk factors. Both the RA twins and their non-affected co-twins had significantly lower mtDNA CN than non-affected twins (−28.7 and −23.1 mtDNA CN, respectively). Adjusting for cell count attenuated these differences (−23.1 mtDNA CN and −20.1 mtDNA CN respectively). Within RA discordant twin pairs PTPN22(T) positive RA twins had a significantly lower amount than their co-twins (−16.3 mtDNA CN). PTPN22(T) had no effect among twins from non-affected twin pairs. MtDNA CN is significantly lower in persons with established RA and in predisposed non-affected RA co-twins suggesting that mitochondrial variation may be involved in the RA disease pathways. Our results also suggest that the RA associated genetic risk factor, PTPN22(T), further decreases the mtDNA CN, but only in carriers with established RA.

Background Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). Conclusions Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.

Epigenetic mechanisms that can influence gene expression include histone acetylation and DNA methylation. This chapter reviews epigenetic studies of MZ twin pairs discordant for a history of cancer. Each of the eight published papers identified by systematic search compared levels of methylation in DNA from blood, saliva and/or skin fibroblasts between affected and cancer-free members of each twin pair. The number of twin pairs examined ranged from 1 to 41. These studies had two general objectives: investigating the hypothesis that differential DNA methylation could be responsible for discordant phenotypes of genetically identical twin pairs, and discovery of biomarkers for early detection of disease. Limitations that will need to be addressed in future studies of this type include small sample size, relevance of tissue tested to target tissue, artifact that could arise from differential mixtures of cell types, and timing of the sample collection with respect to diagnosis and treatment. The studies reviewed here illustrate the rationale whereby observational studies of epigenetic state in phenotype-discordant MZ twin pairs may contribute uniquely to both etiologic and clinical-translational research.

Objectives: To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein.Methods: Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels.Results: IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins.Conclusion: EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.

Publisher Copyright: © 2021 The Authors We studied the association between episodic memory and cortical fibrillar β-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of 1415 twin pairs in a population-based older Finnish Twin Cohort study, we identified 45 (mean [SD] age 72.9 [4.0] years, 40% women) cognitively discordant same-sex twin pairs (24 dizygotic and 21 monozygotic) without neurological or psychiatric disorders other than AD or mild cognitive impairment. In-person neuropsychological testing was conducted. Cortical amyloid was measured with carbon 11-labelled Pittsburgh compound B ([11C]PiB) positron emission tomography imaging and quantified as the average standardized uptake value ratio in cortical regions affected in AD. Larger within-twin pair differences in verbal immediate (r = -0.42) and delayed free recall (r = -0.41), and visual delayed free recall (r = -0.46) were associated with larger within-twin pair differences in [11C]PiB uptake (p's < 0.01). Correlations were not significantly different in dizygotic and monozygotic pairs suggesting that the episodic memory-cortical amyloid relationship is not confounded by genetic effects. However, larger samples are needed to draw more definitive conclusions.

BackgroundFoetal development indicates the risk of later disease, but has only been associated with few psychiatric disorders. An aggregated molecular marker of development - DNA methylation based estimates of gestational age (DNAmGA) adjusted for GA, can be indicative of foetal health and development. Twins have the same chronological GA and monozygotic (MZ) twins share genetic liability. We leveraged this to examine whether DNAmGA in neonates associate with later psychiatric disorder, independent of chronological GA, maternal characteristics, genetic influences, and shared environmental factors.MethodWe estimated DNAmGA in 260 MZ and 396 dizygotic (DZ) twin pairs, later diagnosed with schizophrenia, bipolar disorder, affective/depressive mood disorder, autism spectrum disorder, attention deficit hyperactivity disorder or anorexia. DNAmGA was tested for association with psychiatric outcome by mean discordant twin differences and by linear mixed model (LMM), adjusting for relatedness and potential confounders.ResultsWe found elevated DNAmGA to associate with anorexia between discordant DZ and MZ twins (0.74 weeks, 95%CI[0.34:1.14] and 0.28 weeks, 95%CI[0.04:0.53], respectively), and with bipolar disorder between discordant MZ twins (0.85 weeks, 95%CI[0.16:1.53]). Elevated DNAmGA associated significantly with both in the LMM analysis (0.56 weeks, 95%CI[0.32:0.83] and 0.89 weeks, 95%CI[0.32:1.51], respectively).ConclusionsElevated DNAmGA is associated with two later onset psychiatric disorders in twins, and thus supports a developmental origin of disease. This association was not confounded by variation in conventional measures of foetal development nor genetic liability. We therefore propose that a novel molecular marker of development, can differentiate between later psychiatric outcome in newborn twins.

RationaleEarly-life antibiotic use has been associated with the development of atopic diseases, but the aetiology remains unclear. To elucidate the aetiology, we used a discordant twin design to control for genetic and environmental confounding.MethodsWe conducted a retrospective cohort study in twins aged 3–10 years from the Netherlands Twin Register (NTR, n=35 365) and a replication study in twins aged 9 years from the Childhood and Adolescent Twin Study in Sweden (CATSS, n=7916). Antibiotic use was recorded at age 0–2 years. Doctor-diagnosed asthma and eczema were reported by parents when children were aged 3–12 years in both cohorts. Individuals were included in unmatched analyses and in co-twin control analyses with disease discordant twin pairs.ResultsEarly-life antibiotic use was associated with increased risk of asthma (NTR OR 1.34, 95% CI 1.28–1.41; CATSS OR 1.45, 95% CI 1.34–1.56) and eczema (NTR OR 1.08, 95% CI 1.03–1.13; CATSS OR 1.07, 95% CI 1.01–1.14) in unmatched analyses. Co-twin analyses in monozygotic and dizygotic twin pairs showed similar results for asthma (NTR OR 1.54, 95% CI 1.20–1.98; CATSS OR 2.00, 95% CI 1.28–3.13), but opposing results for eczema in the NTR (OR 0.99, 95% CI 0.80–1.25) and the CATSS (OR 1.67, 95% CI 1.12–2.49). The risk of asthma increased for antibiotics prescribed for respiratory infections (CATSS OR 1.45, 95% CI 1.34–1.56), but not for antibiotics commonly used for urinary tract/skin infections (CATSS OR 1.02, 95% CI 0.88–1.17).ConclusionChildren exposed to early-life antibiotic use, particularly prescribed for respiratory infections, may be at higher risk of asthma. This risk can still be observed when correcting for genetic and environmental factors. Our results could not elucidate whether the relationship between early-life antibiotic use and eczema is confounded by familial and genetic factors.

Alzheimer’s disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18 kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer’s disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer’s disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72–77 years) underwent [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([11C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014–17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer’s disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ∼20% higher cortical [11C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05–0.37, P = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer 11[11C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer’s disease process.

We investigated the associations between health behaviors and sustainable working life outcomes including allcause disability pension, disability pensions due to musculoskeletal and mental diagnoses and unemployment. The role of familial factors behind these associations was studied by analysing discordant twin pairs. Our data included Swedish twins born in 1925-1986 (51891 twin individuals). Baseline data based on two independent surveys in 1998-2003 and 2005-2006 for health behaviors were linked to national registers on disability pension and unemployment until 2016. Cox proportional hazards models for hazard ratios (HR) with 95% confidence intervals (CI) were estimated for the whole sample adjusting for covariates. Analyses of health behavior discordant twin pairs (n = 5903 pairs) were conducted using conditional Cox models. In the whole cohort, the combination of healthy behaviors was associated with lower risk for all-cause disability pension, disability pension due to musculoskeletal diagnoses or mental diagnoses, and for unemployment (HRs 0.56-0.86, 95% CIs 0.51-0.92) as did being physically active (HRs 0.69-0.87, 95% CI 0.65-0.92). The discordant pair analyses confirmed the lower risk among those having healthy behaviors (HR 0.70-0.86) or being physically active (HR 0.86-0.87) for all-cause disability pension, disability pension due to musculoskeletal diagnoses, and for unemployment. To conclude, controlling the effects of covariates or familial confounding (i.e. discordant twin pair analyses) shows that being physically active or having several healthy behaviors predict better working life outcomes. This points towards independent association between healthy behavior and longer working life.

Aim: This study was to evaluate the applicability of Doppler velocimetry to determine its correlation with fetal outcome in dichorionic twin pregnancies. Material and methods: Doppler examination of the umbilical artery (UA) and middle cerebral artery (MCA) was performed in 57 twin pairs. Abnormal values of the umbilical artery pulsatility index (PI), umbilical artery Resistive index (RI) were above the 95th percentile and below 5th percentile for the Middle cerebral artery pulsatility index (MCA PI) and Middle cerebral artery resistivity index (MCA RI) for gestational week. The difference of UA PI ≥0.5 in twin pairs was considered abnormal. Results: 33 subjects had a fetal discordance of greater than 15%. Birth weight was found to be significantly lower in subjects with Umbilical artery PI greater than 95th percentile for gestational age (p=0.014). Abnormal MCA RI (P=0.018) and Umbilical artery RI values above 95th percentile was significantly associated with increased risk of IUGR (intra uterine growth restriction) (P=0.036) and NICU (Neonatal intensive care unit) admission (P=0.005). Increased Umbilical artery PI values above 95th percentile was significantly associated with IUGR (P=0.003). Increased Umbilical Artery systolic/diastolic ratio above 95th percentile was significantly associated with IUGR (P=0.002), NICU admission (P=0.026) and still birth (P=0.026). Abnormal cerebra-umbilical ratio ( 0.5) was significantly correlated with increased degree of birth weight discordance of the twins, IUGR (P=0.001) and still birth (P=0.001). Conclusion: Abnormal Doppler values in discordant twin fetus are more likely to be associated with abnormal fetal outcome.

Background A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results In the discordant twin analysis, three genes showed evidence for DE at FDR IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals.

Contains fulltext : 219581.pdf (Publisher’s version ) (Open Access) Background: The use of illicit substances is correlated, meaning that individuals who use one illicit substance are more likely to also use another illicit substance. This association could (partly) be explained by overlapping genetic factors. Genetic overlap may indicate a common underlying genetic predisposition, or can be the result of a causal association. Methods: Polygenic scores for lifetime cannabis use were generated in a sample of Dutch participants (N = 8348). We tested the association of a PGS for cannabis use with ecstasy, stimulants and a broad category of illicit drug use. To explore the nature of the relationship: (1) these analyses were repeated separately in cannabis users and non-users and (2) monozogytic twin pairs discordant for cannabis use were compared on their drug use. Results: The lifetime prevalence was 24.8% for cannabis, 6.2% for ecstasy, 6.5% for stimulants and 7.1% for any illicit drug use. Significant, positive associations were found between PGS for cannabis use with ecstasy use, stimulants and any illicit drug use. These associations seemed to be stronger in cannabis users compared to non-users for both ecstasy and stimulant use, but only in people born after 1968 and not significant after correction for multiple testing. The discordant twin pair analyses suggested that cannabis use could play a causal role in drug use. Conclusions: The genetic liability underlying cannabis use significantly explained variability in ecstasy, stimulant and any illicit drug use. Further research should further explore the underlying mechanism to understand the nature of the association. 6 p.

Background Sick leave due to mental disorders is common. We investigated if sick leave due to mental disorders increased the risk of reoccurring sick leave, disability pension, unemployment, in- and specialized outpatient care, and mortality, using a co-twin design, taking genetics and shared environment (familial factors) into account. Methods The register-based open cohort studies contained twin pairs 18-64 years old discordant for sick leave due to a mental disorder. First, 2202 pairs were followed up to 8 years from the end of the sick leave spell for reoccurring sick leave, disability pension and unemployment. Second, 4979 twin pairs were followed up to 9 years from the beginning of the sick leave spell for death, inpatient and specialized outpatient care. Conditional Cox proportional hazard regression, adjusting for familial factors, was used to calculate Hazard Ratios (HR) with 95% Confidence Intervals (CI). Results Those with sick leave due to mental disorders had 3.64 (CI: 3.24-4.08) times higher risk of reoccurring sick leave the first two years and the first year, they had 12.24 (CI: 8.11-18.46) times the risk for disability pension. The risk of unemployment was 1.99 (CI: 1.72-2.31). The HR for inpatient care was 1.90 (CI: 1.66-2.17) among men but lower among women. For men the risk of outpatient care was higher the first 2 years (HR: 2.08, CI: 1.87-2.31), and for women the HR was 1.57 (CI: 1.47-1.68) for the whole study time. There was an increased risk of death among men (HR: 2.91, CI: 1.70-4.99), but not among women. Conclusions By adjusting for familial factors we could investigate if the same factors that predispose to sick leave due to mental disorders also predispose to morbidity, mortality and unemployment and hence explain the associations. But, sick leave due to mental disorders was associated with a higher risk of work related and health outcomes, independent of familial factors. The risks varied over time and differed among women and men.

This study aimed to compare obstetrical complications and neonatal outcomes between monochorionic and dichorionic discordant twin pregnancies.We enrolled 296 patients with twin pregnancy who delivered at Busan Paik Hospital between January 2014 and December 2017. The prevalence of obstetrical complications, neonatal mortality between monochorionic and dichorionic twins was compared. We also investigated whether there is a difference in neonatal outcome and neonatal morbidity between monochorionic discordant twins without monochorionic-specific complications and dichorionic discordant twins.The risk of fetal deathRisk of birth weight discordance is higher in monochorionic twin but no significant difference was observed in maternal outcomes, neonatal mortality and morbidity between noncomplicated monochorionic and dichorionic discordant twins.

We aimed to investigate the associations of long-term leisure-time physical inactivity, body mass index (BMI) change, and education with sitting time in a 35-year follow-up based on self-reports in surveys. Influences of working status in 2011 and familial confounding on the associations were tested. Data were based on the population-based Finnish Twin Cohort of 5232 twins (53-67-year-old, 41% men) with four surveys in 1975-2011. Statistical analyses were performed using linear regression with several covariates. The effect of familial confounding (genetics and shared environment) was analyzed using a co-twin control design which should be interpreted as if familial confounding plays a role, an association should be seen among all individuals but not in discordant twin pairs. Compared to those not at work, those at work had a longer total sitting time/d. For those at work, higher education was associated with more total sitting but with less non-work sitting. Long-term leisure-time physical inactivity was associated with more non-work sitting among those at work, whereas long-term weight gain with more total and non-work sitting regardless of working status. Familial confounding attenuated the associations, except for the association of increasing BMI with total and non-work sitting among women at work. To conclude, total sitting time was longer among those still at work, but it was also influenced by long-term leisure-time physical inactivity, higher education, and an increase of BMI over the years. Public health efforts should be targeted to reduce sedentary behavior by promoting life-long leisure-time physical activity and weight control.

Approximately 12% of U.S. adults have type 2 diabetes (T2D). Diagnosed T2D is caused by a combination of genetic and environmental factors including age and lifestyle. In adults 45 years and older, the Discordant Twin (DISCOTWIN) consortium of twin registries from Europe and Australia showed a moderate-to-high contribution of genetic factors of T2D with a pooled heritability of 72%. The purpose of this study was to investigate the contributions of genetic and environmental factors of T2D in twins 45 years and older in a U.S. twin cohort (Washington State Twin Registry, WSTR) and compare the estimates to the DISCOTWIN consortium. We also compared these estimates with twins under the age of 45. Data were obtained from 2692 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs over 45 and 4217 twin pairs under 45 who responded to the question ‘Has a doctor ever diagnosed you with (type 2) diabetes?’ Twin similarity was analyzed using both tetrachoric correlations and structural equation modeling. Overall, 9.4% of MZ and 14.7% of DZ twins over the age of 45 were discordant for T2D in the WSTR, compared to 5.1% of MZ and 8% of DZ twins in the DISCOTWIN consortium. Unlike the DISCOTWIN consortium in which heritability was 72%, heritability was only 52% in the WSTR. In twins under the age of 45, heritability did not contribute to the variance in T2D. In a U.S. sample of adult twins, environmental factors appear to be increasingly important in the development of T2D.

Purpose Since twin pairs with discordance have equal gestational age (GA), discordant twins may constitute an appropriate group to investigate the specific effect that birth weight (BW) has on the development of retinopathy of prematurity (ROP). The present study aims to investigate the effect of BW on any and severe stages of ROP development in twin pairs. Methods Fifty-two discordant twin pairs (104 preterms) born ≤32 gestational weeks, who were diagnosed with a minimum of 18% discordance between their BWs, were retrospectively analyzed. Twin pairs were separated into two groups based on the BW of each pair. The rate of any stage of ROP, Type 1 ROP, and perinatal risk factors were compared statistically among twin pairs. Results The rate of any stage of ROP and Type 1 ROP was 24.0% and 4.8% in the whole group, respectively. A statistically significant difference was shown between lower and higher BW groups at any stage of ROP development (34.6% vs. 13.4%, P = 0.02). However, no difference was observed in Type 1 ROP development (7.7% vs. 1.9%, P = 0.17). No significant differences were found between twin pairs regarding neonatal morbidities. The number of small GA (SGA) infants in the smaller twin group was statistically higher than larger group and regression analysis showed that being SGA had significant correlation with any stage of ROP (odds ratio: 4.98, P = 0.02). Conclusion This study showed that BW serves an effective role at any stage of ROP development in discordant twin pairs; however, no significant difference in terms of Type 1 ROP.

Background: Discordant malformation between monochorionic twins is a rare and unknown phenomenon.Objectives: To estimate the incidence of discordant monochorionic twins and to describe their characteristics.Study design: A retrospective multicenter cohort of pregnancies between 2002 and 2015 in La Reunion Island was analyzed, thanks to a population-based register. Only monochorionic pregnancies were included in order to analyze specifically monozygotic twins. We defined as discordant twin pairs those in which different malformations were identified for each twin and those with only one fetus showing a malformation.Results: During the study period, 203,807 births occurred, including 410 monochorionic twin pairs. Congenital anomalies rate for monochorionic twin pairs was 10.7%. We included 38 monochorionic twin pairs with discordant phenotypes, which represent 9.3% of monochorionic twin pairs and 86.4% of monochorionic twin pairs affected by congenital anomalies. Among them, both twins were affected by different congenital anomalies in 7 pairs (18.4%), and only one twin was affected in 31 pairs (81.6%). We identified 20 congenital heart anomalies (44.4%), 5 brain anomalies (11.1%), 5 genital anomalies (11.1%), 4 axial bones and skull anomalies (8.9%), 4 limb anomalies (8.9%), 4 facial anomalies (8.9%), 3 urological anomalies (6.6%), 2 thoracic anomalies (4.4%), 1 bile duct anomaly (2,2%), 1 abdominal parietal defect (2.2%), and 1 aneuploidy (2.2%). Among them, 3 (6.6%) fetuses had an association of malformations. Among the 45 fetuses with malformations, 37 fetuses (82.2%) were born alive and 21 (46.6%) had postnatal surgery.Conclusions: Despite a supposed identical genome, discordant congenital anomalies in monochorionic twin pregnancies are not exceptional and related to genetic and epigenetic mechanisms. Sonographers and pediatricians should know that in monochorionic twin a pair, the occurrence of discordant phenotypes is high (9.3%).