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.
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Acknowledgements
The authors are grateful to all of the families for participating in the AGP, as well as the principal investigators, AGRE and the AGP funders: Autism Speaks (USA), the Medical Research Council (UK), the Health Research Board (Ireland), the National Institutes of Health (USA), Genome Canada, the Canadian Institutes of Health Research and the Hilibrand Foundation. The AGP data sets can be obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap. The authors are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A Beaudet, R Bernier, J Constantino, E Cook, E Fombonne, D Geschwind, R Goin-Kochel, E Hanson, D Grice, A Klin, D Ledbetter, C Lord, C Martin, D Martin, R Maxim, J Miles, O Ousley, K Pelphrey, B Peterson, J Piggot, C Saulnier, M State, W Stone, J Sutcliffe, C Walsh, Z Warren and E Wijsman), and appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org. In particular, We acknowledge S Sanders for his help with the SSC data. We acknowledge the support of the Trinity Centre for High Performance Computing. SC acknowledges the funding received from a Trinity College Dublin Studentship Award.
Summary data results are available at http://www.gwascentral.org/study/HGVST1842.
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Connolly, S., Anney, R., Gallagher, L. et al. A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3. Eur J Hum Genet 25, 234–239 (2017). https://doi.org/10.1038/ejhg.2016.153
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DOI: https://doi.org/10.1038/ejhg.2016.153
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