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A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3.

ABSTRACT: Autism spectrum disorder (ASD) is known to be a heritable neurodevelopmental disorder affecting more than 1% of the population but in the majority of ASD cases, the genetic cause has not been identified. Parent-of-origin effects have been highlighted as an important mechanism in the pathology of neurodevelopmental disorders such as Prader-Willi and Angelman syndrome, with individuals with these syndromes often exhibiting ASD symptoms. Consequently, systematic investigation of these effects in ASD is clearly an important line of investigation in elucidating the underlying genetic mechanisms. Using estimation of maternal, imprinting and interaction effects using multinomial modelling (EMIM), we simultaneously investigated imprinting, maternal genetic effects and associations in the Autism Genome Project and Simons Simplex Consortium genome-wide association data sets. To avoid using the overly stringent genome-wide association study significance level, we used a Bayesian threshold that takes into account the sample size, allele frequency and any available prior knowledge. Between the two data sets, we identified a total of 18 imprinting effects and 68 maternal genetic effects that met this Bayesian threshold criteria, but none met the threshold in both data sets. We identified imprinting and maternal genetic effects for regions that have previously shown evidence for parent-of-origin effects in ASD. Together with these findings, we have identified maternal genetic effects not previously identified in ASD at a locus in SHANK3 on chromosome 22 and a locus in WBSCR17 on chromosome 7 (associated with Williams syndrome). Both genes have previously been associated with ASD.

SUBMITTER: Connolly S

PROVIDER: S-EPMC5255953 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3.

Connolly Siobhan S Anney Richard R Gallagher Louise L Heron Elizabeth A EA

European journal of human genetics : EJHG 20161123 2

Autism spectrum disorder (ASD) is known to be a heritable neurodevelopmental disorder affecting more than 1% of the population but in the majority of ASD cases, the genetic cause has not been identified. Parent-of-origin effects have been highlighted as an important mechanism in the pathology of neurodevelopmental disorders such as Prader-Willi and Angelman syndrome, with individuals with these syndromes often exhibiting ASD symptoms. Consequently, systematic investigation of these effects in AS ...[more]

PMID: 27876814

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Project description:Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018, 11: 587-601. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY:Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication.

Dataset Information

A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3.

Publications

A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3.

Similar Datasets

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