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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 coexpression 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 that translational regulation by FMRP and transcriptional coregulation 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 biological framework for further investigating the pathophysiology of ASD.

SUBMITTER: Parikshak NN

PROVIDER: S-EPMC3934107 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.

Parikshak Neelroop N NN Luo Rui R Zhang Alice A Won Hyejung H Lowe Jennifer K JK Chandran Vijayendran V Horvath Steve S Geschwind Daniel H DH

Cell 20131101 5

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 coexpression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical ...[more]

PMID: 24267887

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Project description:BackgroundParkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed "Lewy Bodies" within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking.MethodsThis study employed two state-of-the-art technologies, three-stage Mass Spectrometry Tandem Mass Tag Proteomics (12 PD, 12 controls) and RNA-sequencing transcriptomics (29 PD, 44 controls), evaluated in the context of PD GWAS implicated loci and microarray transcriptomics (19 PD, 24 controls). The technologies applied for this study were performed in a set of overlapping prefrontal cortex (Brodmann area 9) samples obtained from PD patients and sex and age similar neurologically healthy controls.ResultsAfter appropriate filters, proteomics robustly identified 3558 unique proteins, with 283 of these (7.9 %) significantly different between PD and controls (q-value < 0.05). RNA-sequencing identified 17,580 protein-coding genes, with 1095 of these (6.2 %) significantly different (FDR p-value < 0.05); only 166 of the FDR significant protein-coding genes (0.94 %) were present among the 3558 proteins characterized. Of these 166, eight genes (4.8 %) were significant in both studies, with the same direction of effect. Functional enrichment analysis of the proteomics results strongly supports mitochondrial-related pathways, while comparable analysis of the RNA-sequencing results implicates protein folding pathways and metallothioneins. Ten of the implicated genes or proteins co-localized to GWAS loci. Evidence implicating SNCA was stronger in proteomics than in RNA-sequencing analyses.ConclusionsWe report the largest analysis of proteomics in PD to date, and the first to combine this technology with RNA-sequencing to investigate GWAS implicated loci. Notably, differentially expressed protein-coding genes were more likely to not be characterized in the proteomics analysis, which lessens the ability to compare across platforms. Combining multiple genome-wide platforms offers novel insights into the pathological processes responsible for this disease by identifying pathways implicated across methodologies.

Dataset Information

Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.

Publications

Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.

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