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Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

ABSTRACT: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

SUBMITTER: Satterstrom FK

PROVIDER: S-EPMC7250485 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

Satterstrom F Kyle FK Kosmicki Jack A JA Wang Jiebiao J Breen Michael S MS De Rubeis Silvia S An Joon-Yong JY Peng Minshi M Collins Ryan R Grove Jakob J Klei Lambertus L Stevens Christine C Reichert Jennifer J Mulhern Maureen S MS Artomov Mykyta M Gerges Sherif S Sheppard Brooke B Xu Xinyi X Bhaduri Aparna A Norman Utku U Brand Harrison H Schwartz Grace G Nguyen Rachel R Guerrero Elizabeth E EE Dias Caroline C Betancur Catalina C Cook Edwin H EH Gallagher Louise L Gill Michael M Sutcliffe James S JS Thurm Audrey A Zwick Michael E ME Børglum Anders D AD State Matthew W MW Cicek A Ercument AE Talkowski Michael E ME Cutler David J DJ Devlin Bernie B Sanders Stephan J SJ Roeder Kathryn K Daly Mark J MJ Buxbaum Joseph D JD

Cell 20200123 3

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained t ...[more]

PMID: 31981491

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Project description:BackgroundDisrupted cortical connectivity is thought to underlie the complex cognitive and behavior profile observed in individuals with autism spectrum disorder (ASD). Previous neuroimaging research has identified patterns of both functional hypo- and hyper-connectivity in individuals with ASD. A recent theory attempting to reconcile conflicting results in the literature proposes that hyper-connectivity of brain networks may be more characteristic of young children with ASD, while hypo-connectivity may be more prevalent in adolescents and adults with the disorder when compared to typical development (TD) (Uddin etal., 2013). Previous work has examined only young children, mixed groups of children and adolescents, or adult cohorts in separate studies, leaving open the question of developmental influences on functional brain connectivity in ASD.MethodsThe current study tests this developmental hypothesis by examining within- and between-network resting state functional connectivity in a large sample of 26 children, 28 adolescents, and 18 adults with ASD and age- and IQ-matchedTD individuals for the first time using an entirely data-driven approach. Independent component analyses (ICA) and dual regression was applied to data from three age cohorts to examine the effects of participant age on patterns of within-networkwhole-brain functional connectivity in individuals with ASD compared with TD individuals. Between-network connectivity differences were examined for each age cohort by comparing correlations between ICA components across groups.ResultsWe find that in the youngest cohort (age 11 and under), children with ASD exhibit hyper-connectivity within large-scale brain networks as well as decreased between-network connectivity compared with age-matchedTD children. In contrast, adolescents with ASD (age 11-18) do not differ from TD adolescents in within-network connectivity, yet show decreased between-network connectivity compared with TD adolescents. Adults with ASD show no within- or between-network differences in functional network connectivity compared with neurotypical age-matched individuals.ConclusionsCharacterizing within- and between-network functional connectivity in age-stratified cohorts of individuals with ASD and TD individuals demonstrates that functional connectivity atypicalities in the disorder are not uniform across the lifespan. These results demonstrate how explicitly characterizing participant age and adopting a developmental perspective can lead to a more nuanced understanding of atypicalities of functional brain connectivity in autism.

Dataset Information

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

Publications

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

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