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      The bidirectional association between sleep problems and autism spectrum disorder: a population-based cohort study

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          Abstract

          Background

          Sleep difficulties are prevalent in children with autism spectrum disorder (ASD). The temporal nature of the association between sleep problems and ASD is unclear because longitudinal studies are lacking. Our aim is to clarify whether sleep problems precede and worsen autistic traits and ASD or occur as a consequence of the disorder.

          Methods

          Repeated sleep measures were available at 1.5, 3, 6, and 9 years of age in 5151 children participating in the Generation R Study, a large prospective birth cohort in the Netherlands. Autistic traits were determined with the Pervasive Developmental Problems score (PDP) of the Child Behavior Checklist (CBCL) at 1.5 and 3 years and the Social Responsiveness Scale (SRS) at 6 years. This cohort included 81 children diagnosed with ASD.

          Results

          Sleep problems in early childhood were prospectively associated with a higher SRS score, but not when correcting for baseline PDP score. By contrast, a higher SRS score and an ASD diagnosis were associated with more sleep problems at later ages, even when adjusting for baseline sleep problems. Likewise, a trajectory of increasing sleep problems was associated with ASD.

          Conclusions

          Sleep problems and ASD are not bidirectionally associated. Sleep problems do not precede and worsen autistic behavior but rather co-occur with autistic traits in early childhood. Over time, children with ASD have an increase in sleep problems, whereas typically developing children have a decrease in sleep problems. Our findings suggest that sleep problems are part of the construct ASD.

          Electronic supplementary material

          The online version of this article (10.1186/s13229-018-0194-8) contains supplementary material, which is available to authorized users.

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          Most cited references53

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          Structural variation of chromosomes in autism spectrum disorder.

          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            Executive Functions and Developmental Psychopathology

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              The epidemiology of autism spectrum disorders.

              Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. They are much more common than previously believed, second in frequency only to mental retardation among the serious developmental disorders. Although a heritable component has been demonstrated in ASD etiology, putative risk genes have yet to be identified. Environmental risk factors may also play a role, perhaps via complex gene-environment interactions, but no specific exposures with significant population effects are known. A number of endogenous biomarkers associated with autism risk have been investigated, and these may help identify significant biologic pathways that, in turn, will aid in the discovery of specific genes and exposures. Future epidemiologic research should focus on expanding population-based descriptive data on ASDs, exploring candidate risk factors in large well-designed studies incorporating both genetic and environmental exposure data and addressing possible etiologic heterogeneity in studies that can stratify case groups and consider alternate endophenotypes.
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                Author and article information

                Contributors
                m.verhoeff@erasmusmc.nl
                l.blanken@erasmusmc.nl
                d.kocevska@erasmusmc.nl
                viara.mileva@gmail.com
                v.jaddoe@erasmusmc.nl
                t.white@erasmusmc.nl
                f.verhulst@erasmusmc.nl
                Luijk@fsw.eur.nl
                h.tiemeier@erasmusmc.nl
                Journal
                Mol Autism
                Mol Autism
                Molecular Autism
                BioMed Central (London )
                2040-2392
                30 January 2018
                30 January 2018
                2018
                : 9
                : 8
                Affiliations
                [1 ]ISNI 000000040459992X, GRID grid.5645.2, The Generation R Study Group, , Erasmus Medical Center, ; Rotterdam, the Netherlands
                [2 ]GRID grid.416135.4, Department of Child and Adolescent Psychiatry/Psychology, , Erasmus University Medical Center–Sophia Children’s Hospital, ; 2060, Rotterdam, 3000 CB the Netherlands
                [3 ]GRID grid.416135.4, Department of Pediatrics, , Erasmus University Medical Center–Sophia Children’s Hospital, ; Rotterdam, the Netherlands
                [4 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Epidemiology, , Erasmus University Medical Center, ; Rotterdam, the Netherlands
                [5 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Radiology, , Erasmus University Medical Center, ; Rotterdam, the Netherlands
                [6 ]ISNI 0000000092621349, GRID grid.6906.9, Department of Psychology, Education and Child Studies, , Erasmus University Rotterdam, ; Rotterdam, the Netherlands
                [7 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Psychiatry, , Erasmus University Medical Center, ; Rotterdam, the Netherlands
                Article
                194
                10.1186/s13229-018-0194-8
                5791216
                29423134
                c0213b46-f801-48a0-aea5-684f770748bf
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 April 2017
                : 16 January 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003246, Nederlandse Organisatie voor Wetenschappelijk Onderzoek;
                Award ID: 016.VICI.170.200
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003061, Erasmus Medisch Centrum;
                Award ID: Mrace
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: 2013-2548/001-001-EMA-2
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000893, Simons Foundation;
                Award ID: SFARI - 307280
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                autism,sleep problems,bidirectional,birth cohort,general population
                Neurosciences
                autism, sleep problems, bidirectional, birth cohort, general population

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