| 1. |
- Arora, M., et al.
(författare)
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Fetal and postnatal metal dysregulation in autism
- 2017
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Ingår i: Nat Commun. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings.
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| 2. |
- Austin, C, et al.
(författare)
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Dynamical properties of elemental metabolism distinguish attention deficit hyperactivity disorder from autism spectrum disorder
- 2019
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 238-
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Tidskriftsartikel (refereegranskat)abstract
- Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions of overlapping etiologies and phenotypes. For ASD, we recently reported altered elemental metabolic patterns in the form of short and irregular zinc and copper cycles. Here, we extend the application of these biomarkers of prenatal and early postnatal elemental metabolism to distinguish between individuals diagnosed with ADHD and/or ASD and neurotypical controls. We recruited twins discordant for ADHD, ASD and other neurodevelopmental diagnoses from national twin studies in Sweden (N = 74) diagnosed according to DSM-5 clinical consensus and standardized psychiatric instruments. Detailed temporal profiles of exposure to 10 metals over the prenatal and early childhood periods were measured using tooth biomarkers. We used recurrence quantification analysis (RQA) to characterize properties of cyclical metabolic patterns of these metals. Regularity (determinism) and complexity (entropy) of elemental cycles was consistently reduced in ADHD for cobalt, lead, and vanadium (determinism: cobalt, β = −0.03, P = 0.017; lead, β = −0.03, P = 0.016; and vanadium, β = −0.03, P = 0.01. Entropy: cobalt, β = −0.13, P = 0.017; lead, β = −0.18, P = 0.016; and vanadium, β = −0.15, P = 0.008). Further, we found elemental pathways and dynamical features specific to ADHD vs ASD, and unique characteristics associated with ADHD/ASD combined presentation. Dysregulation of cyclical processes in elemental metabolism during prenatal and early postnatal development not only encompasses pathways shared by ADHD and ASD, but also comprise features specific to either condition.
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| 3. |
- Bolte, S., et al.
(författare)
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The Roots of Autism and ADHD Twin Study in Sweden (RATSS)
- 2014
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Ingår i: Twin Research and Human Genetics. - Stockholm : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 17:3, s. 164-176
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Tidskriftsartikel (refereegranskat)abstract
- Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.
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| 4. |
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| 5. |
- Avdic, H. B., et al.
(författare)
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Reduced effects of social feedback on learning in Turner syndrome
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Turner syndrome is a genetic condition caused by a complete or partial loss of one of the X chromosomes. Previous studies indicate that Turner syndrome is associated with challenges in social skills, but the underlying mechanisms remain largely unexplored. A possible mechanism is a reduced social influence on learning. The current study examined the impact of social and non-social feedback on learning in women with Turner syndrome (n=35) and a sex- and age-matched control group (n=37). Participants were instructed to earn points by repeatedly choosing between two stimuli with unequal probabilities of resulting in a reward. Mastering the task therefore required participants to learn through feedback which of the two stimuli was more likely to be rewarded. Data were analyzed using computational modeling and analyses of choice behavior. Social feedback led to a more explorative choice behavior in the control group, resulting in reduced learning compared to non-social feedback. No effects of social feedback on learning were found in Turner syndrome. The current study thus indicates that women with Turner syndrome may be less sensitive to social influences on reinforcement learning, than the general population.
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| 6. |
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| 7. |
- Willfors, C., et al.
(författare)
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On the role of non-shared environment for executive functioning in ADHD: a twin-differences design study
- 2014
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Ingår i: International Journal of Developmental Disabilities. - : Informa UK Limited. - 2047-3869 .- 2047-3877. ; 60:3, s. 163-173
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The study of differences between monozygotic (MZ) twin pairs with respect to ADHD may provide novel leads to disentangle the environmental contribution driving its phenotypes. Objectives: To examine non-shared environmental influences on executive function in dimensionally defined ADHD. Methods: This study included 27 MZ twin pairs (7 female) aged 11-20 years being moderately to substantially discordant for ADHD traits as assessed by the Attention Problem (AP) scale of the Child Behavior Checklist/Adult Behavior Checklist. The twins completed the Wisconsin Card Sorting Test (WCST) for cognitive flexibility and the Tower Test (TT) for foresighted planning. Two statistical approaches were used to analyze the data. First, correlations between ADHD trait intra-pair differences and WCST and TT scores were calculated. Second, the significance of those intra-pair differences on WCST and TT, using ADHD as categorical variable in clinically discordant pairs, was tested. Results: Both analysing strategies revealed a link between ADHD on one hand, and foresighted planning and inhibitory control on the other hand mediated by non-shared environmental factors. The first statistical approach yielded positive correlations between intra-pairs differences on the AP scale and intra-pair differences on two subscales of the TT: total rule violation (r(s)=0.41) and rule-violation-per-item-ratio (r(s)=0.38). Findings in categorically discordant pairs were consistent, showing within-pair differences on the same subtests (z-1.63, P=0.05, one-tailed and z=-1.60, P=0.05, one-tailed). Conclusions: Findings confirm previous research suggesting ADHD to be a quantitative extreme on a continuum with executive functions being a cognitive marker of ADHD traits. Non-shared environmental factors appear to influence planning skills and inhibitory control.
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| 8. |
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| 9. |
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| 10. |
- Becker, M, et al.
(författare)
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Presynaptic dysfunction in CASK-related neurodevelopmental disorders
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 312-
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Tidskriftsartikel (refereegranskat)abstract
- CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.
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| 11. |
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| 13. |
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| 14. |
- Isaksson, Johan, et al.
(författare)
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Social Cognition in Autism and Other Neurodevelopmental Disorders : A Co-twin Control Study
- 2019
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Ingår i: Journal of autism and developmental disorders. - : Springer Science and Business Media LLC. - 0162-3257 .- 1573-3432. ; 49:7, s. 2838-2848
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in social cognition (SC) are hypothesized to underlie social communication and interaction challenges in autism spectrum disorder (ASD). The aetiological underpinnings driving this association remain unclear. We examined SC in 196 twins with ASD, other neurodevelopmental disorders or typical development using the naturalistic Movie for the Assessment of Social Cognition. Autism and its severity were assessed with the Autism Diagnostic Observation Schedule-2, and autistic traits with the Social Responsiveness Scale-2. Using within twin-pair regression models, controlling for age, sex, IQ, and unmeasured familial confounders such as genetic background and shared-environment, SC correlated with ASD diagnosis, autism severity, and autistic traits. Our findings highlight the importance of SC alterations in autism and suggest a non-shared environmental impact on the association.
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| 15. |
- Lundin Kleberg, Johan, et al.
(författare)
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Williams syndrome : reduced orienting to other's eyes in a hypersocial phenotype
- 2023
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Ingår i: Journal of autism and developmental disorders. - : Springer Nature. - 0162-3257 .- 1573-3432. ; 53:7, s. 2786-2797
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Tidskriftsartikel (refereegranskat)abstract
- Williams syndrome (WS) is a rare genetic condition associated with high sociability, intellectual disability, and social cognitive challenges. Attention to others' eyes is crucial for social understanding. Orienting to, and from other’s eyes was studied in WS (n = 37, mean age = 23, age range 9–53). The WS group was compared to a typically developing comparison participants (n = 167) in stratified age groups from infancy to adulthood. Typically developing children and adults were quicker and more likely to orient to eyes than the mouth. This bias was absent in WS. The WS group had reduced peak saccadic velocities, indicating hypo-arousal. The current study indicates reduced orienting to others’ eyes in WS, which may affect social interaction skills.
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| 16. |
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| 17. |
- Neufeld, Janina, et al.
(författare)
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Global and local visual processing in autism - a co-twin-control study
- 2020
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Ingår i: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 61:4, s. 470-479
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autism Spectrum Disorder (ASD) is associated with altered global and local visual processing. However, the nature of these alterations remains controversial, with contradictory findings and notions ranging from a reduced drive to integrate information into a coherent 'gestalt' ("weak central coherence" = WCC) to an enhanced perceptual functioning (EPF) in local processing.METHODS: This study assessed the association between autism and global/local visual processing, using a large sample of monozygotic (MZ) and dizygotic (DZ) twins (N = 290, 48% females, age = 8-31 years). The Fragmented Pictures Test (FPT) assessed global processing, whereas local processing was estimated with the Embedded Figures Test (EFT) and the Block Design Test (BDT). Autism was assessed both categorically (clinical diagnosis), and dimensionally (autistic traits). Associations between visual tasks and autism were estimated both across the cohort and within-twin pairs where all factors shared between twins are implicitly controlled.RESULTS: Clinical diagnosis and autistic traits predicted a need for more visual information for gestalt processing in the FPT across the cohort. For clinical diagnosis, this association remained within-pairs and at trend-level even within MZ twin pairs alone. ASD and higher autistic traits predicted lower EFT and BDT performance across the cohort, but these associations were lost within-pairs.CONCLUSIONS: In line with the WCC account, our findings indicate an association between autism and reduced global visual processing in children, adolescents and young adults (but no evidence for EPF). Observing a similar association within MZ twins suggests a non-shared environmental contribution.
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| 18. |
- Stamouli, S, et al.
(författare)
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Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders
- 2018
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Ingår i: Twin research and human genetics : the official journal of the International Society for Twin Studies. - : Cambridge University Press (CUP). - 1832-4274. ; 21:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.
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| 19. |
- Willfors, C, et al.
(författare)
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Medical history of discordant twins and environmental etiologies of autism
- 2017
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:1, s. e1014-
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Tidskriftsartikel (refereegranskat)abstract
- The environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=−2.85, P=0.004) and autistic traits (β=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.
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| 20. |
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