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Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders.

ABSTRACT: In recent years, a large number of studies around the world have led to the identification of causal genes for hereditary types of common and rare neurological and psychiatric disorders.To explore the functional and genomic features of known human genes mutated in neuropsychiatric disorders.A systematic search was used to develop a comprehensive catalog of genes mutated in neuropsychiatric disorders (NPD). Functional enrichment and protein-protein interaction analyses were carried out. A false discovery rate approach was used for correction for multiple testing.We found several functional categories that are enriched among NPD genes, such as gene ontologies, protein domains, tissue expression, signaling pathways and regulation by brain-expressed miRNAs and transcription factors. Sixty six of those NPD genes are known to be druggable. Several topographic parameters of protein-protein interaction networks and the degree of conservation between orthologous genes were identified as significant among NPD genes.These results represent one of the first analyses of enrichment of functional categories of genes known to harbor mutations for NPD. These findings could be useful for a future creation of computational tools for prioritization of novel candidate genes for NPD.

SUBMITTER: Forero DA

PROVIDER: S-EPMC5120378 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders.

Forero Diego A DA Prada Carlos F CF Perry George G

The open neurology journal 20161111

<h4>Background</h4>In recent years, a large number of studies around the world have led to the identification of causal genes for hereditary types of common and rare neurological and psychiatric disorders.<h4>Objective</h4>To explore the functional and genomic features of known human genes mutated in neuropsychiatric disorders.<h4>Methods</h4>A systematic search was used to develop a comprehensive catalog of genes mutated in neuropsychiatric disorders (NPD). Functional enrichment and protein-pro ...[more]

PMID: 27990183

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Project description:OBJECTIVE:Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed). METHOD:The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome. RESULTS:Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3). CONCLUSIONS:The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

Dataset Information

Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders.

Publications

Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders.

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