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Prioritized High-Confidence Risk Genes for Intellectual Disability Reveal Molecular Convergence During Brain Development.

ABSTRACT: Dissecting the genetic susceptibility to intellectual disability (ID) based on de novo mutations (DNMs) will aid our understanding of the neurobiological and genetic basis of ID. In this study, we identify 63 high-confidence ID genes with q-values < 0.1 based on four background DNM rates and coding DNM data sets from multiple sequencing cohorts. Bioinformatic annotations revealed a higher burden of these 63 ID genes in FMRP targets and CHD8 targets, and these genes show evolutionary constraint against functional genetic variation. Moreover, these ID risk genes were preferentially expressed in the cortical regions from the early fetal to late mid-fetal stages. In particular, a genome-wide weighted co-expression network analysis suggested that ID genes tightly converge onto two biological modules (M1 and M2) during human brain development. Functional annotations showed specific enrichment of chromatin modification and transcriptional regulation for M1 and synaptic function for M2, implying the divergent etiology of the two modules. In addition, we curated 12 additional strong ID risk genes whose molecular interconnectivity with known ID genes (q-values < 0.3) was greater than random. These findings further highlight the biological convergence of ID risk genes and help improve our understanding of the genetic architecture of ID.

SUBMITTER: Liu Z

PROVIDER: S-EPMC6153320 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Prioritized High-Confidence Risk Genes for Intellectual Disability Reveal Molecular Convergence During Brain Development.

Liu Zhenwei Z Zhang Na N Zhang Yu Y Du Yaoqiang Y Zhang Tao T Li Zhongshan Z Wu Jinyu J Wang Xiaobing X

Frontiers in genetics 20180918

Dissecting the genetic susceptibility to intellectual disability (ID) based on <i>de novo</i> mutations (DNMs) will aid our understanding of the neurobiological and genetic basis of ID. In this study, we identify 63 high-confidence ID genes with <i>q</i>-values < 0.1 based on four background DNM rates and coding DNM data sets from multiple sequencing cohorts. Bioinformatic annotations revealed a higher burden of these 63 ID genes in FMRP targets and CHD8 targets, and these genes show evolutionar ...[more]

PMID: 30279698

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Project description:BackgroundMicroarray analysis has been used as the first-tier genetic testing to detect chromosomal imbalances and copy number variants (CNVs) for pediatric patients with intellectual and developmental disabilities (ID/DD). To further investigate the candidate genes and underlying dosage-sensitive mechanisms related to ID, cytogenomic mapping of critical regions and bioinformatic mining of candidate brain-expressed genes (BEGs) and their functional interactions were performed. Critical regions of chromosomal imbalances and pathogenic CNVs were mapped by subtracting known benign CNVs from the Databases of Genomic Variants (DGV) and extracting smallest overlap regions with cases from DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). BEGs from these critical regions were revealed by functional annotation using Database for Annotation, Visualization, and Integrated Discovery (DAVID) and by tissue expression pattern from Uniprot. Cross-region interrelations and functional networks of the BEGs were analyzed using Gene Relationships Across Implicated Loci (GRAIL) and Ingenuity Pathway Analysis (IPA).ResultsOf the 1,354 patients analyzed by oligonucleotide array comparative genomic hybridization (aCGH), pathogenic abnormalities were detected in 176 patients including genomic disorders in 66 patients (37.5%), subtelomeric rearrangements in 45 patients (25.6%), interstitial imbalances in 33 patients (18.8%), chromosomal structural rearrangements in 17 patients (9.7%) and aneuploidies in 15 patients (8.5%). Subtractive and extractive mapping defined 82 disjointed critical regions from the detected abnormalities. A total of 461 BEGs was generated from 73 disjointed critical regions. Enrichment of central nervous system specific genes in these regions was noted. The number of BEGs increased with the size of the regions. A list of 108 candidate BEGs with significant cross region interrelation was identified by GRAIL and five significant gene networks involving cell cycle, cell-to-cell signaling, cellular assembly, cell morphology, and gene expression regulations were denoted by IPA.ConclusionsThese results characterized ID related cross-region interrelations and multiple networks of candidate BEGs from the detected genomic imbalances. Further experimental study of these BEGs and their interactions will lead to a better understanding of dosage-sensitive mechanisms and modifying effects of human mental development.

Project description:Sleep has been strongly implicated in learning and especially in the reprocessing of recently acquired memory. Children with intellectual disability (ID) tend to have sleep-wake disturbances, which may contribute to the pathophysiology of the disease. As far as sleep is, in part, a circadian process, we decided to study rhythmic gene expression in hippocampus, a brain structure, which plays a key role in memory in human and rodents. By investigating the transcriptome of mouse adult hippocampus, we report here the identification of 663 circadian rhythm (CR)-regulated genes, which have been clustered in four categories, based on their temporal pattern of expression. In addition to the standard core-clock genes, enrichment analysis of the hippocampal CR-regulated genes revealed the presence of several transcription factors, underlying the existence of an inter-regulation of genes' expression between clusters. Interestingly, these hippocampal circadian rhythm-regulated genes are very enriched in sleep/wakefulness related genes. We show here that glucocorticoid signaling, already shown to be involved in memory regulation, is a circadian regulated pathway in hippocampus. Furthermore, we identified a list of 30 CR-regulated ID genes. Our results demonstrate that hippocampus can be considered as a peripheral oscillator and illustrate the link between circadian rhythm, sleep, intellectual disability and memory consolidation. In order to identify circadian rhythm-regulated genes in mouse hippocampus, we realized a study in dark-dark conditions, thus allowing to overcome the effects induced by light changes. To systematically identify genes with circadian regulated expression, RNA samples from the hippocampus of three mice at four Circadian Time (CT) points were used for expression profiling using Agilent microarray technology. The dark/dark period started at 7 p.m. The Circadian Time (CT) 18 samples were taken after 30 h of continuous dark; the other circadian times followed at 6-h intervals: CT0, CT6 and CT12 after 36, 42 and 48 h of continuous darkness, respectively.

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Prioritized High-Confidence Risk Genes for Intellectual Disability Reveal Molecular Convergence During Brain Development.

Publications

Prioritized High-Confidence Risk Genes for Intellectual Disability Reveal Molecular Convergence During Brain Development.

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