Discordant Twins Research Articles

Comparing the potential causal influence of two indicators of early alcohol use on later alcohol use disorder symptoms.

Age of first drink (AFD) has repeatedly been found to be associated with alcohol use disorder (AUD); however, some studies suggest this is a noncausal effect that may be due to childhood risk factors or familial influences. In contrast to indicators of any early alcohol use, such as AFD, indicators of a pattern of repeated drinking may be more likely to be causally associated with later problematic alcohol use. The current study examined AFD and age of onset of regular drinking (ARD; defined as drinking at least once a month for 6 or more months) as quasicausal predictors of lifetime AUD symptoms. Participants were 3,005 adult Australian twins who reported having been regular drinkers in their lifetime. Semistructured interviews were conducted to assess AFD, ARD, AUD, externalizing symptomatology, and other substance use. Personality traits were assessed via questionnaire. Unadjusted and adjusted multilevel discordant twin models were conducted using data from 1,041 complete twin pairs; adjusted models included socioeconomic status, personality, conduct disorder, and early initiation of regular smoking and marijuana use as covariates. Results from fully adjusted models controlling for familial confounds provided evidence for a causal influence of ARD on AUD symptoms, whereby twins with an earlier age of regular drinking than their cotwin had more lifetime AUD symptoms. However, AFD did not significantly predict AUD symptoms after adjusting for confounds. These results suggest that early regular drinking may serve as a causal risk factor for future problems, while early initiation of any alcohol use may indicate genetic liability. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Longitudinal neurodevelopmental outcomes in preterm twins.

Several factors contribute to neurodevelopmental outcomes in preterm infants. The aim of this study was to examine the genetic and environmental influences on long-term outcomes in preterm twins. From a prospective cohort of 225 preterm neonates studied with MRI, 24 monozygotic and 52 dizygotic twins were included. Neurodevelopmental outcomes at 1.5 and 3 years were assessed with the Bayley-III and at 4.5 years with The Movement Assessment Battery for Children and The Wechsler Preschool and Primary Scale of Intelligence-III. Preterm monozygotic and dizygotic twin pairs (N = 76 neonates) had similar neurodevelopmental outcomes at all time points. Monozygotic twins (N = 24) did not show greater agreement for outcomes relative to dizygotic twins (N = 52). Twin pairs who were discordant in development (N = 12) were born at a lower gestational age and had a higher incidence of bronchopulmonary dysplasia and retinopathy of prematurity. Discordant twins become more similar in cognitive and language outcomes over time. Neurodevelopmental outcomes in preterm twins may relate more strongly to environmental factors than genetics. Discordant twins were born earlier and had more perinatal morbidities. Despite the initial discordance, these twin pairs become similar in outcomes over time, which may reflect the positive impact of home environment or early intervention programs. Neurodevelopmental outcomes in preterm twins relate more strongly to environmental factors than genetics. Monozygotic twins did not show greater agreement in outcomes relative to dizygotic twins suggesting a stronger environmental, rather than genetic, influence on development. Twin pairs who were discordant in development were born at a lower gestational age and had a higher incidence of perinatal morbidities. Despite the initial discordance, these twin pairs become more similar in cognitive and language outcomes over time, which may reflect the positive impact of early intervention programs or home environment. Neurodevelopmental outcomes in preterm twins are influenced by exposure to early-life insults or environmental stressors. The initial variability in outcomes among preterm infants is not fixed, and efforts made post-discharge from the neonatal intensive care unit can have a substantial impact on long-term outcomes.

Early-life antibiotic use and risk of asthma and eczema: results of a discordant twin study.

Early-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. We 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. Early-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). Children 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.

Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.

Retinopathy of prematurity in discordant twins: is the small twin at increased risk?

To examine the effect of birth weight (BW) independent of gestational age (GA) on Retinopathy of prematurity (ROP) in preterm discordant twins. A retrospective cohort study of 45 preterm twin pairs born at < 34weeks of gestation with BW discordance of ≥ 20%. The twin pairs were divided into two groups based on BW - small or large. Rates of ROP, stage, treatment, and prognosis were compared between the two groups. Other neonatal outcomes related to prematurity were also compared between groups. The mean gestation age at delivery was 31.1weeks of gestation. The rate of ROP was significantly higher among the smaller twins compared to the larger twins (8.9% vs 0% respectively, p = 0.04). All smaller twins with ROP had stage 2 disease, and all cases of ROP had resolved without treatment. Regarding neonatal morbidities, the smaller twins had longer hospitalization length (53.8 vs 39.4days respectively, p < 0.01) and a higher rate of hypoglycemia (55.6% vs 24.4% respectively, p = 0.003), whereas the larger twins were more commonly affected by respiratory distress syndrome (59.1% vs 26.7% respectively, p = 0.002). The rate of ROP was higher among the small twins in preterm discordant twins. This may indicate that low BW rather than early GA is the main factor contributing to the development of ROP.

Epigenetic Methods and Twin Studies.

Genomic predisposition fails to fully explain the onset of complex diseases, which is well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and non-coding RNA, are the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. Autoimmune diseases now include almost 100 conditions and are estimated to cumulatively affect up to 5% of the world population with a healthcare expenditure superior to cancer worldwide. Many advances in medicine have been made to treat these conditions but there are still gaps, and an innovative and efficient therapy is needed. Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, polymyositis, and dermatomyositis. Monozygotic twins discordant for any disease offer an ideal study design as they are matched for many factors, including genetic variation and this is a real advantage for epigenetics study. We will herein discuss the available data in the epigenetic differences leading to disease discordance in MZ twins for systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.

Association of neuroinflammation with episodic memory: a [11C]PBR28 PET study in cognitively discordant twin pairs.

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.

Supplemental Material for Sex Differences in the Relative Influence of Marital Status and Parenthood on Alcohol Use Disorder Symptoms: A Multilevel Discordant Twin Design

Supplemental Material for Sex Differences in the Relative Influence of Marital Status and Parenthood on Alcohol Use Disorder Symptoms: A Multilevel Discordant Twin Design

On the Nature of Monozygotic Twin Concordance and Discordance for Autistic Trait Severity: A Quantitative Analysis

The characterizing features of autism spectrum disorder (ASD) are continuously distributed in nature; however, prior twin studies have not systematically incorporated this knowledge into estimations of concordance and discordance. We conducted a quantitative analysis of twin–twin similarity for autistic trait severity in three existing data sets involving 366 pairs of uniformly-phenotyped monozygotic (MZ) twins with and without ASD. Probandwise concordance for ASD was 96%; however, MZ trait correlations differed markedly for pairs with ASD trait burden below versus above the threshold for clinical diagnosis, with R2s on the order of 0.6 versus 0.1, respectively. Categorical MZ twin discordance for ASD diagnosis is rare and more appropriately operationalized by standardized quantification of twin–twin differences. Here we provide new evidence that although ASD itself is highly heritable, variation-in-severity of symptomatology above the diagnostic threshold is substantially influenced, in contrast, by non-shared environmental factors which may identify novel targets of early ASD amelioration.

Considerations on genetic engineering: regarding the birth of twins subjected to gene edition.

In this essay, the bioethical implications of the recent genetic manipulation in human embryos with CRISPR-Cas9 to eliminate the CCR5 gene and the birth of a pair of discordant twin girls are analyzed. The experiment was disseminated via social media. The main bioethical flaws identified include the justification of the model, the informed consent process and the lack of disclosure of evident conflicts of interest. The consequences of the experiment on the life of the twins that were born were not properly evaluated, such as the impact on their autonomy, the alleged benefits to be received and the future risks of harm during their lifetime. Having manipulated the germ cell line, the effects on their future offspring were not considered. This type of actions negatively affects the way society conceives science. Genetic engineering should be reserved to the basic experimental context or as clinical research for the correction of known serious diseases of genetic origin under strict regulatory and bioethical supervision and using a gradualist approach in accordance with the advances of gene editing techniques.

Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis.

Background: Adolescent idiopathic scoliosis (AIS) is a complex disease affecting a large number of teenagers, especially in female. This study reveals novel epigenetic perturbation to the pathogenesis of AIS.Methods: A female monozygotic (MZ) twin pair discordant for AIS were examined for whole-exome sequencing and epigenome difference. Sets of differentially methylated regions (DMRs) were validated using MethylTarget™ method in 20 AIS female patients and 20 healthy female controls.Results: Few exome difference but several potential DMRs were found between the MZ twins. We identified 313 hypermethylated DMRs and 397 hypomethylated DMRs, respectively. Most of them were enriched in the MAPK and PI3K-Akt signaling pathway, which may contribute to the discordance of AIS. Several DMRs related to scoliosis genes were tested, and the NDN: TSS-DMR (chr15:23932133-23932304, hg19) was confirmed in additional samples. The methylation level of this DMR was significantly higher in the AIS group than in the control group (p = 0.04).Conclusions: We described the epigenome difference in an AIS female discordant MZ twin pair using Whole Genome Bisulfite Sequencing (WGBS). The NDN: TSS-DMR had higher methylation level in female AIS, which can help elucidate the potential etiology of AIS.

Health, work and demographic factors associated with a lower risk of work disability and unemployment in employees with lower back, neck and shoulder pain

BackgroundChronic musculoskeletal pain affects over 20% of the adult population and is one of the most common reasons for sick leave in Sweden. The aim of this study was to investigate which demographic, health and psychosocial work environment factors are of importance for a lower risk of future work disability and unemployment among workers with low back pain (LBP) and/or neck shoulder pain (NSP), and if familial factors influence these associations.MethodsAll 5556 persons that reported having LBP and/or NSP in a web-based questionnaire study in 2004–2006 were included. They were followed up for work disability (sick leave > 90 days or disability pension), and unemployment (> 180 days in a year) until 31 December 2013. Hazard ratios (HR) with 95% confidence intervals were calculated using cox proportional hazard models of the whole sample, adjusting for covariates. In addition, co-twin analyses of outcome discordant twin pairs were conducted to assess the impact of familial confounding on the associations.ResultsBeing male, 19–28 years old, having higher education, only NSP, no history of depression or anxiety, good self-rated health, low job demands and high job control were associated with a lower risk of work disability (adjusted HR ranging between 0.29–0.85). No history of anxiety and depression and high job control was associated with a lower risk of unemployment (adjusted HR ranging from 0.53 and 0.67). Familial factors were found to affect the association between education and work disability, but none of the other associations investigated.ConclusionsAmong those with LBP or NSP, good health in terms of mental- and self-rated health, few pain sites, as well as good psychosocial working conditions seem to indicate a lower risk for work disability.

Pervasive Inter-Individual Variation in Allele-Specific Expression in Monozygotic Twins

Despite being developed from one zygote, heterokaryotypic monozygotic (MZ) co-twins exhibit discordant karyotypes. Epigenomic studies in biological samples from heterokaryotypic MZ co-twins are of the most significant value for assessing the effects on gene- and allele-specific expression of an extranumerary chromosomal copy or structural chromosomal disparities in otherwise nearly identical germline genetic contributions. Here, we use RNA-Seq data from existing repositories to establish within-pair correlations for the breadth and magnitude of allele-specific expression (ASE) in heterokaryotypic MZ co-twins discordant for trisomy 21 and maternal 21q inheritance, as well as homokaryotypic co-twins. We show that there is a genome-wide disparity at ASE sites between the heterokaryotypic MZ co-twins. Although most of the disparity corresponds to changes in the magnitude of biallelic imbalance, ASE sites switching from either strictly monoallelic to biallelic imbalance or the reverse occur in few genes that are known or predicted to be imprinted, subject to X-chromosome inactivation or A-to-I(G) RNA edited. We also uncovered comparable ASE differences between homokaryotypic MZ twins. The extent of ASE discordance in MZ twins (2.7%) was about 10-fold lower than the expected between pairs of unrelated, non-twin males or females. The results indicate that the observed within-pair dissimilarities in breadth and magnitude of ASE sites in the heterokaryotypic MZ co-twins could not solely be attributable to the aneuploidy and the missing allelic heritability at 21q.

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation

BackgroundA 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.MethodsGenome-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.ResultsIn the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including 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.LimitationsIdentical 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.ConclusionsUsing 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.

Early childhood head injury attenuates declines in impulsivity and aggression across adolescent development in twins.

Head injury during development has been associated with behavioral changes such as impulsivity and antisocial behavior. This study investigates the extent to which behavioral changes associated with childhood head injury are sustained through adolescence and emerging adulthood. Survey data was collected at 5 waves spanning 12 years (ages 9-20) from the University of Southern California Risk Factors for Antisocial Behavior twin study. Impulsivity was measured by errors of commission in a Go/NoGo behavioral task, and aggression was measured through youth self-report using the Reactive-Proactive Aggression Questionnaire. Head injury was assessed retrospectively using caregiver questionnaires at twin ages 14-15 years and self-reported at ages 19-20 years. Participants with a head injury in early childhood showed significant delay in the normative developmental decline of impulsivity relative to the noninjured by mid-adolescence (ages 14-15.) Moreover, earlier age at injury was related to a slower decrease in impulsivity and greater increase in reactive aggression scores. Finally, among discordant monozygotic twin pairs, the twin with a head injury experienced significantly less decline in impulsivity by ages 19-20 than the noninjured co-twin. These findings indicate early childhood head injury may play a significant role in blunting the decline in impulsivity across development, exposing an additional risk factor for antisocial behavior. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Adverse outcomes of sick leave due to mental disorders: prospective studies of discordant twin pairs

Abstract 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.

Risk factors of disability pensions – what will twin studies from Finland and Sweden add?

Abstract Background Finland and Sweden have been forerunners to investigate social insurance in twin cohorts. Using twin cohorts to research disability pension (DP) has provided a unique possibility to control for genetic and environmental factors (i.e. familial confounding). This is important, since genetics is known to play an important role in many chronic diseases for DP such as low back pain (30%), depression (40%) and a moderate (35-48 %) role in DP. Furthermore, familial confounding can be expected to affect many risk factors, i.e. health and behavior related factors and is therefore of interest in the associations between risk factors and DP. Methods In twin cohort studies for DP, first, the twins are treated as singletons, and the effect of risk factors on the incidence of DP is analyzed by applying regression models. Second, analyzing twin pairs discordant for both outcome (DP) and risk factors provides a possibility to control for familial confounding. This co-twin-control design is a unique tool, includes investigation whether twins who are exposed to a specific factor of interest more often are granted a DP than their non-exposed co-twins. Results Co-twin control design allows adjustment for familial confounding. Therefore, the results based on discordant twin pairs add to the epidemiological findings of unrelated subjects. Based on population-based twin cohort studies with long follow-up, indications exist that the familial confounding may have different role in the association between risk factors and DP depending on risk factors of interest but also on diagnosis group for DP. Conclusions Evidently the underlying medical condition is important, and the risk factors vary between diagnosis groups of DP. However, also familial factors play a role in process of sickness absence, in the transition from sickness absence to DP, and for DP. Therefore, need for early identification of risk factors and tailored interventions of prevention is emerged for public health.

Associations of sitting time with leisure-time physical inactivity, education, and body mass index change.

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.

Single cell transcriptome in aneuploidies reveals mechanisms of gene dosage imbalance

Aneuploidy is a major source of gene dosage imbalance due to copy number alterations (CNA), and viable human trisomies are model disorders of altered gene expression. We study gene and allele-specific expression (ASE) of 9668 single-cell fibroblasts from trisomy 21 (T21) discordant twins and from mosaic T21, T18, T13 and T8. We examine 928 single cells with deep scRNAseq. Expected and observed overexpression of trisomic genes in trisomic vs. diploid bulk RNAseq is not detectable in trisomic vs. diploid single cells. Instead, for trisomic genes with low-to-average expression, their altered gene dosage is mainly due to the higher fraction of trisomic cells simultaneously expressing these genes, in agreement with a stochastic 2-state burst-like model of transcription. These results, confirmed in a further analysis of 8740 single fibroblasts with shallow scRNAseq, suggest that the specific transcriptional profile of each gene contributes to the phenotypic variability of trisomies. We propose an improved model to understand the effects of CNA and, generally, of gene regulation on gene dosage imbalance.

Modifiable environmental factors – Role and impact of (including evidence for intervention)

It is now generally accepted that multiple sclerosis (MS) is a multifactorial disease occurring in genetically susceptible individuals upon exposure to environmental factors. The importance of environmental factors in MS is supported by discordance in monozygotic twins, geographical distribution of MS prevalence, migration studies, increase in MS incidence and changes of gender ratio over time, among others. Robust evidence supports the role of EBV, smoking, UV radiation/vitamin D and obesity during adolescence as environmental factors. Some evidence also suggests the involvement of other factors such as night shift work, organic solvents, concussions, salt intake, melatonin, parasites, coffee and alcohol consumption as well as dysbiosis of the gut microbiome. Environmental factors play a role not only in the susceptibility to develop MS but also in disease activity and disability progression. Furthermore, it has been shown that environmental factors interact among one another and with genetic factors. Whether there is a critical time period during which exposure to these factors is most important is still not fully understood. However, modifying these factors once MS is established might still have an impact in the disease course, as is the case of smoking cessation. Overall, this suggests that interventions directed towards modifying environmental and lifestyle factors could prevent some MS cases and improve the prognosis in MS patients. However, our understanding of the underlying pathogenic mechanisms of these factors and the impact of their modification is still limited. Future research to identify other environmental factors and to investigate the impact of intervention over known environmental factors is necessary.