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1.
  • Sha, ZQ, et al. (författare)
  • Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium
  • 2022
  • Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 27:4, s. 2114-2125
  • Tidskriftsartikel (refereegranskat)abstract
    • Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.
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  • Jonsson, Lina, 1982, et al. (författare)
  • Examining neurodevelopmental problems in 15q11.2 (BP1-BP2) copy number variation carriers at ages 9/12 and 18 in a Swedish twin sample
  • 2023
  • Ingår i: Molecular Genetics & Genomic Medicine. - 2324-9269. ; 11:8
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundSeveral copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1-BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population-based sample of children. MethodsTwins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs). ResultsWe identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self-reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs. ConclusionsOur results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children.
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  • Myers, L, et al. (författare)
  • Actionable and incidental neuroradiological findings in twins with neurodevelopmental disorders
  • 2020
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 22417-
  • Tidskriftsartikel (refereegranskat)abstract
    • While previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.
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  • Myers, L., et al. (författare)
  • Variable neurodevelopmental and morphological phenotypes of carriers with 12q12 duplications
  • 2020
  • Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal duplications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature. Methods We report a phenotypic description of a family with monozygotic twins diagnosed with NDDs, carrying a 9 Mb duplication at 12q12, and five other individuals with overlapping duplications ranging from 4.54 Mb up to 15.16 Mb. Results The duplication carriers had language delays, cognitive delays, and were diagnosed with autism spectrum disorder. Additionally, distinct facial features (e.g., high foreheads, deeply set eyes, short palpebral fissures, small ears, high nasal bridges, abnormalities of the nose tip, thin lips), large feet, and abnormalities in the digits were noted. We also describe incomplete penetrance of the NDD phenotypes among the individuals with 12q12 duplication. Conclusion This case series expands our knowledge on this rare genetic aberration and suggests that large 12q12 duplications may increase the risk for developing NDDs.
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  • Becker, M, et al. (författare)
  • Presynaptic dysfunction in CASK-related neurodevelopmental disorders
  • 2020
  • Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 312-
  • 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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  • Chan, AJS, et al. (författare)
  • Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
  • 2022
  • Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6463-
  • Tidskriftsartikel (refereegranskat)abstract
    • Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorize 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We develop a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD have a significantly higher GRVS compared to those with nondysmorphic ASD (P = 0.03). Using the polygenic transmission disequilibrium test, we observe an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P = 2.9 × 10−3). These findings replicate using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.
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  • Coviello, D, et al. (författare)
  • Essential information on genetic testing methods that each clinician needs to know/understand
  • 2021
  • Ingår i: EUROPEAN PSYCHIATRY. - : Royal College of Psychiatrists. - 0924-9338 .- 1778-3585. ; 64, s. S49-S50
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Genetic testing is well established in many areas of clinical medicine, is increasingly used in clinical psychiatry and it becomes increasingly important to understand the scope and limitations of the different genetic tests applied. The recommended genetic work-up of patients with neurodevelopmental disorders (such as intellectual disability or autism spectrum disorders) includes conventional karyotyping (low resolution) able to detect chromosomal rearrangement and structural variants (>5Mb, 5 million-bp), testing for fragile X-Syndrome, screening for deletions and duplications down to 20 Kb by Comparative Genomic Hybridisation (CGH), able to detect Copy Number Variation (CNVs; gain or loss of genetic material compared to the reference genome). Sanger sequencing is used for mapping of single base pair genetic variants in single genes but unable to identify deletions or duplications. The more advanced Next Generation Sequencing (NGS) have enabled to detect variants in panels of 10-100 (or more) genes, or in all coding regions using Whole Exome Sequencing (WES; 23.000 genes). Whole Genome Sequencing (WGS) analysis enables also the detection of all size range and types of genetic variation including CNVs, trinucleotide repeats and translocations. All this led to an impressive change in interpreting genomic variants that need to be strictly linked to clinical information before it can be used by clinicians to improve diagnosis or care. Bioinformatic tools to annotate variants, predict their effects and select the genes and genomic regions of interest are needed to guide the clinical work followed with careful evaluation of the prioritized variants based on the clinical knowledge (https://www.cost.eu/actions/CA17130/#tabs|Name:overview).No significant relationships.
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  • Falck-Ytter, Terje, et al. (författare)
  • The Babytwins Study Sweden (BATSS): A Multi-Method Infant Twin Study of Genetic and Environmental Factors Influencing Infant Brain and Behavioral Development
  • 2021
  • Ingår i: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 24:4, s. 217-227
  • Tidskriftsartikel (refereegranskat)abstract
    • Twin studies can help us understand the relative contributions of genes and environment to phenotypic trait variation, including attentional and brain activation measures. In terms of applying methodologies such as electroencephalography (EEG) and eye tracking, which are key methods in developmental neuroscience, infant twin studies are almost nonexistent. Here, we describe the Babytwins Study Sweden (BATSS), a multi-method longitudinal twin study of 177 MZ and 134 DZ twin pairs (i.e., 622 individual infants) covering the 5-36 month time period. The study includes EEG, eye tracking and genetics, together with more traditional measures based on in-person testing, direct observation and questionnaires. The results show that interest in participation in research among twin parents is high, despite the comprehensive protocol. DNA analysis from saliva samples was possible in virtually all participants, allowing for both zygosity confirmation and polygenic score analyses. Combining a longitudinal twin design with advanced technologies in developmental cognitive neuroscience and genomics, BATSS represents a new approach in infancy research, which we hope to have impact across multiple disciplines in the coming years.
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13.
  • Hellquist, A, et al. (författare)
  • Access, utilization, and awareness for clinical genetic testing in autism spectrum disorder in Sweden: A survey study
  • 2022
  • Ingår i: Autism : the international journal of research and practice. - : SAGE Publications. - 1461-7005. ; 26:7, s. 1795-1804
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical genetic testing is recommended for individuals diagnosed with autism spectrum disorder. There are only a few reports of how these recommendations are followed and especially missing for European countries. We aimed to analyze the rate of access, utilization, and awareness of clinical genetic testing among autistic individuals in Sweden through online surveys targeting parents with at least one autistic child and autistic adolescents (from 15 years) and adults. In total, 868 parents of autistic children and 213 autistic adolescents or adults completed the survey. Only 9.1% ( n = 79) of parents and 2.8% ( n = 6) of autistic adolescents/adults reported having received a referral for clinical genetic testing after autism spectrum disorder diagnosis. The autistic children offered a referral were younger at diagnosis ( p < 0.001) and more likely to have an additional neurodevelopmental diagnosis ( p < 0.01), including intellectual disability ( p < 0.001) or a language disorder ( p < 0.001). Genetic counseling was provided to less than half of the families that were referred for clinical genetic testing. Finally, we report that both respondent groups preferred to be informed by written text and an expert in genetics about clinical genetic testing. This study highlights a lack of awareness and access to clinical genetic testing after autism spectrum disorder diagnosis in Sweden and demonstrates the need for additional studies on how clinical guidelines for genetic testing are followed in different countries. Several medical professional societies recommend clinical genetic testing for autistic individuals as many genetic conditions are linked to autism. However, it is unclear to what extent autistic individuals and parents of autistic children are offered clinical genetic testing. We conducted a community-based survey to estimate the access, utilization, and awareness for clinical genetic testing in Sweden. In total, 868 parents of autistic children and 213 autistic adolescents or adults participated as respondents. The referral rate for clinical genetic testing after autism spectrum disorder diagnosis was low, with only 9.1% for the autistic children as reported by their parents and 2.8% for autistic adolescents/adults. The autistic children who got referrals were more likely to have intellectual disability and language disorder. We also report that awareness of the clinical genetic testing possibility was low in both respondent groups. We also highlight preferred communication means and needs for information before clinical genetic testing. Our results show that utilization and access are low in Sweden, and more studies should be conducted to report these rates in different countries to analyze the effects of clinical genetic testing on healthcare for autistic individuals. Our results highlight the most important information for the families and how the information should be communicated prior to clinical genetic testing.
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  • Pan, PY, et al. (författare)
  • The Association Between Somatic Health, Autism Spectrum Disorder, and Autistic Traits
  • 2020
  • Ingår i: Behavior genetics. - : Springer Science and Business Media LLC. - 1573-3297 .- 0001-8244. ; 50:4, s. 233-246
  • Tidskriftsartikel (refereegranskat)abstract
    • This study used a twin cohort to investigate the association of autism spectrum disorder (ASD) and autistic traits with somatic health. A total of 344 twins (172 pairs; mean age 15.56 ± 5.62 years) enriched for ASD and other neurodevelopmental conditions were examined. Medical history and current physical problems were collected with a validated questionnaire to determine twin’s somatic health. The Social Responsiveness Scale (SRS-2) was used to measure the participant’s severity of autistic traits. Identified somatic health issues with significant within-twin pair differences were tested in relation to both ASD diagnosis and autistic traits in a co-twin control model. Twins with ASD exhibited more neurological and immunological health problems compared to those without ASD (p = 0.005 and p = 0.004, respectively). The intra-pair differences of neurological conditions and SRS-2 score were significantly correlated in monozygotic twins differing for autism traits (r = 0.40, p = 0.001), while the correlation was not found for immunological problems. In addition, a conditional model for analysis of within-twin pair effects revealed an association between neurological problems and clinical ASD diagnosis (Odds ratio per neurological problem 3.15, p = 0.02), as well as autistic traits (β = 10.44, p = 0.006), after adjusting for possible effects of co-existing attention deficit hyperactivity disorder and general intellectual abilities. Our findings suggest that neurological problems are associated with autism, and that non-shared environmental factors contribute to the overlap for both clinical ASD and autistic traits. Further population-based twin studies are warranted to validate our results and examine in detailed the shared genetic and environmental contributions of neurological problems and ASD.
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  • Susanto, Evelyn, et al. (författare)
  • Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells
  • 2020
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:33, s. 20127-20138
  • Tidskriftsartikel (refereegranskat)abstract
    • Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using In-duced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carry-ing a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, en-hanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we dem-onstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.
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  • Swann, J. R., et al. (författare)
  • Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins
  • 2023
  • Ingår i: Neuropharmacology. - : Elsevier. - 0028-3908 .- 1873-7064. ; 234
  • Tidskriftsartikel (refereegranskat)abstract
    • Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins' models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.
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