Integrative Functional Genomic Analyses Implicate Specific Molecular Pathways and Circuits in Autism

Abstract

Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: 1) do these genetic loci converge on specific biological processes, and 2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto co-expression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest translational regulation by FMRP and transcriptional co-regulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a novel biological framework for investigating the pathophysiology of ASD.

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

“…Supporting our above hypothesis is a recent study on specific molecular pathways and circuits in autism, where ASD and ID risk genes were mapped onto co-expression networks of developmental trajectories and transcriptional profiles in the fetal and adult cortical laminae. 34 These studies showed bioinformatically that FMRP interacts with a series of ASD genes, one of them being MBD5. 34 Finally, we show that the expression levels of NR1D2 and CRY2 were significantly reduced in 2q23.1 deletion syndrome, SMS, and FXS LCLs.…”

“…34 These studies showed bioinformatically that FMRP interacts with a series of ASD genes, one of them being MBD5. 34 Finally, we show that the expression levels of NR1D2 and CRY2 were significantly reduced in 2q23.1 deletion syndrome, SMS, and FXS LCLs. Interestingly, loss of CRY2 has been linked to high anxiety, and NR1D2 was recently shown to protect normal metabolic function.…”

Increased burden of deleterious variants in essential genes in autism spectrum disorder

“…Our study is focused on a specific neurodevelopmental disorder-ASD-because it has been suggested that ASD has its roots in abnormalities in prenatal brain development (50)(51)(52). Specifically, our analysis of the temporal expression patterns of coexpressed gene modules in the developing brain shows that genes in three EGenriched coexpression modules implicated in ASD are expressed at a high level at the earliest stages of brain development, as early as 8 weeks after conception.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Co-expression networks seeded with genes recurrently mutated in autism were found to converge with networks in deep layer projection neurons of the prefrontal and primary motorsomatosensory cortex during midfetal development [193]. Parikshak et al [194] mapped autism risk genes to transcriptional networks throughout development and identified glutamatergic neurons in upper cortical layers as a critical cell type and brain region in autism. Undoubtedly, pathway and related network analyses have identified some degree of convergence with regard to potential mechanisms in which genes may participate, but, at present, these mechanisms remain fairly broad.…”