Geschwind DH, Konopka G. Neuroscience in the era of functional genomics and systems biology. Nature 461: 908-915

Program in Neurogenetics and Neurobehavioural Genetics, Department of Neurology and Semel Institute, David Geffen School of Medicine, Los Angeles, California 90095, USA.
Nature (Impact Factor: 41.46). 10/2009; 461(7266):908-15. DOI: 10.1038/nature08537
Source: PubMed

ABSTRACT Advances in genetics and genomics have fuelled a revolution in discovery-based, or hypothesis-generating, research that provides a powerful complement to the more directly hypothesis-driven molecular, cellular and systems neuroscience. Genetic and functional genomic studies have already yielded important insights into neuronal diversity and function, as well as disease. One of the most exciting and challenging frontiers in neuroscience involves harnessing the power of large-scale genetic, genomic and phenotypic data sets, and the development of tools for data integration and mining. Methods for network analysis and systems biology offer the promise of integrating these multiple levels of data, connecting molecular pathways to nervous system function.

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    • "Accordingly, expression analyses of ASD or SCZ risk genes using comprehensive spatiotemporal transcriptomic data from the human brain (Johnson et al., 2009; Colantuoni et al., 2011; Kang et al., 2011), have revealed highly disparate spatial patterns and developmental trajectories. However, gene co-expression network analyses, which can be used to identify clusters of highly correlated genes (Eisen et al., 1998; Stuart et al., 2003; Geschwind and Konopka, 2009), have uncovered key points of convergence in the timing and location of risk gene expression. Expression network analyses of high-confidence ASD loci have identified the mid-fetal neocortex to be a significant point of spatiotemporal intersection (Parikshak et al., 2013; Willsey et al., 2013), suggesting a significant contribution of the developing neocortex to ASD circuit dysfunction (Kwan, 2013). "
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    ABSTRACT: A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.
    Frontiers in Genetics 07/2014; 5:239. DOI:10.3389/fgene.2014.00239
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    • "This resolves a tension between discovery and hypothesis testing. A recent review [22] contrasts ‘-ology’ strategies that typically test a priori hypotheses with ‘-omics’ strategies that adopt more agnostic, exploratory approaches, stressing that “... discovery-based approaches do not eschew hypotheses; rather, they seek to elevate hypothesis testing to a new level, by allowing high-throughput hypothesis generation and prioritization” [22]. "
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    ABSTRACT: Background The Consortium for Neuropsychiatric Phenomics (CNP) at UCLA was an investigation into the biological bases of traits such as memory and response inhibition phenotypes—to explore whether they are linked to syndromes including ADHD, Bipolar disorder, and Schizophrenia. An aim of the consortium was in moving from traditional categorical approaches for psychiatric syndromes towards more quantitative approaches based on large-scale analysis of the space of human variation. It represented an application of phenomics—wide-scale, systematic study of phenotypes—to neuropsychiatry research. Results This paper reports on a system for exploration of hypotheses in data obtained from the LA2K, LA3C, and LA5C studies in CNP. ViVA is a system for exploratory data analysis using novel mathematical models and methods for visualization of variance. An example of these methods is called VISOVA, a combination of visualization and analysis of variance, with the flavor of exploration associated with ANOVA in biomedical hypothesis generation. It permits visual identification of phenotype profiles—patterns of values across phenotypes—that characterize groups. Visualization enables screening and refinement of hypotheses about variance structure of sets of phenotypes. Conclusions The ViVA system was designed for exploration of neuropsychiatric hypotheses by interdisciplinary teams. Automated visualization in ViVA supports ‘natural selection’ on a pool of hypotheses, and permits deeper understanding of the statistical architecture of the data. Large-scale perspective of this kind could lead to better neuropsychiatric diagnostics.
    BioData Mining 07/2014; 7(1):11. DOI:10.1186/1756-0381-7-11 · 2.02 Impact Factor
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    • "Our study identified many significant genes and function pathways overlapped with those previous studies. Further experimental analysis to connect the functional genomics and molecular pathways is required for a better understanding of human brain and nervous system development [33]. "
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    ABSTRACT: Microarray 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). Of 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. These 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.
    Molecular Cytogenetics 01/2014; 7(1):4. DOI:10.1186/1755-8166-7-4 · 2.14 Impact Factor
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