Dataset Information

Brain-specific functional relationship networks inform autism spectrum disorder gene prediction.

ABSTRACT: Autism spectrum disorder (ASD) is a neuropsychiatric disorder with strong evidence of genetic contribution, and increased research efforts have resulted in an ever-growing list of ASD candidate genes. However, only a fraction of the hundreds of nominated ASD-related genes have identified de novo or transmitted loss of function (LOF) mutations that can be directly attributed to the disorder. For this reason, a means of prioritizing candidate genes for ASD would help filter out false-positive results and allow researchers to focus on genes that are more likely to be causative. Here we constructed a machine learning model by leveraging a brain-specific functional relationship network (FRN) of genes to produce a genome-wide ranking of ASD risk genes. We rigorously validated our gene ranking using results from two independent sequencing experiments, together representing over 5000 simplex and multiplex ASD families. Finally, through functional enrichment analysis on our highly prioritized candidate gene network, we identified a small number of pathways that are key in early neural development, providing further support for their potential role in ASD.

SUBMITTER: Duda M

PROVIDER: S-EPMC5838237 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Brain-specific functional relationship networks inform autism spectrum disorder gene prediction.

Duda Marlena M Zhang Hongjiu H Li Hong-Dong HD Wall Dennis P DP Burmeister Margit M Guan Yuanfang Y

Translational psychiatry 20180306 1

Autism spectrum disorder (ASD) is a neuropsychiatric disorder with strong evidence of genetic contribution, and increased research efforts have resulted in an ever-growing list of ASD candidate genes. However, only a fraction of the hundreds of nominated ASD-related genes have identified de novo or transmitted loss of function (LOF) mutations that can be directly attributed to the disorder. For this reason, a means of prioritizing candidate genes for ASD would help filter out false-positive resu ...[more]

PMID: 29507298

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Project description:Many individuals with autism spectrum disorders have comorbid epilepsy. Even in the absence of observable seizures, interictal epileptiform discharges are common in individuals with autism spectrum disorders. However, how these interictal epileptiform discharges are related to autistic symptomatology remains unclear. This study used magnetoencephalography to investigate the relation between interictal epileptiform discharges and altered functional brain networks in children with autism spectrum disorders. Instead of particularly addressing individual brain regions, we specifically examine network properties. For this case-control study, we analysed 70 children with autism spectrum disorders (52 boys, 18 girls, 38-92 months old) and 19 typically developing children (16 boys, 3 girls, 48-88 months old). After assessing the participants' social reciprocity using the Social Responsiveness Scale, we constructed graphs of functional brain networks from frequency band separated task-free magnetoencephalography recordings. Nodes corresponded to Desikan-Killiany atlas-based 68 brain regions. Edges corresponded to phase lag index values between pairs of brain regions. To elucidate the effects of the existence of interictal epileptiform discharges on graph metrics, we matched each of three pairs from three groups (typically developing children, children with autism spectrum disorders who had interictal epileptiform discharges and those who did not) in terms of age and sex. We used a coarsened exact matching algorithm and applied adjusted regression analysis. We also investigated the relation between social reciprocity and the graph metric. Results show that, in children with autism spectrum disorders, the average clustering coefficient in the theta band was significantly higher in children who had interictal epileptiform discharges. Moreover, children with autism spectrum disorders who had no interictal epileptiform discharges had a significantly lower average clustering coefficient in the theta band than typically developing children had. However, the difference between typically developing children and children with autism spectrum disorder who had interictal epileptiform discharges was not significant. Furthermore, the higher average clustering coefficient in the theta band corresponded to severe autistic symptoms in children with autism spectrum disorder who had interictal epileptiform discharges. However, the association was not significant in children with autism spectrum disorders who had no interictal epileptiform discharge. In conclusion, results demonstrate that alteration of functional brain networks in children with autism spectrum disorders depends on the existence of interictal epileptiform discharges. Interictal epileptiform discharges might 'normalize' the deviation of altered brain networks in autism spectrum disorders, increasing the clustering coefficient. However, when the effect exceeds tolerance, it actually exacerbates autistic symptoms.

Dataset Information

Brain-specific functional relationship networks inform autism spectrum disorder gene prediction.

Publications

Brain-specific functional relationship networks inform autism spectrum disorder gene prediction.

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