Genetic and genomic approaches have implicated hundreds of genetic loci in neurodevelopmental disorders and neurodegeneration, but mechanistic understanding continues to lag behind the pace of gene discovery. Understanding the role of specific genetic variants in the brain involves dissecting a functional hierarchy that encompasses molecular pathways, diverse cell types, neural circuits and, ultimately, cognition and behaviour. With a focus on transcriptomics, this Review discusses how high-throughput molecular, integrative and network approaches inform disease biology by placing human genetics in a molecular systems and neurobiological context. We provide a framework for interpreting network biology studies and leveraging big genomics data sets in neurobiology.
At a glance
- Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat. Neurosci. 17, 782–790 (2014).
A comprehensive review of GWASs and exome studies across major neuropsychiatric disorders. It discusses the role of common variants and rare variants across disorders, and the concept of explaining heritability.
, , &
- Integrating physical and genetic maps: from genomes to interaction networks. Nat. Rev. Genet. 8, 699–710 (2007). , &
- Complex brain networks: graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 10, 186–198 (2009). &
- Neuroscience in the era of functional genomics and systems biology. Nature 461, 908–915 (2009). &
- Systems biology in neuroscience: bridging genes to cognition. Curr. Opin. Neurobiol. 13, 577–582 (2003).
- Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nat. Methods 6, 875–881 (2009). et al.
- Neuroscience thinks big (and collaboratively). Nat. Rev. Neurosci. 14, 659–664 (2013). , , , &
- Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res. 41, D996–D1008 (2013). et al.
- A mesoscale connectome of the mouse brain. Nature 508, 207–214 (2014). et al.
- The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
- Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014). et al.
- An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012). et al.
- Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011). et al.
- Roadmap Epigenomics Consortium. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).
- The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013). et al.
- Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17, 1418–1428 (2014).
A large eQTL study across multiple brain regions that identified region-specific eQTLs and demonstrated the value and promise of eQTL analysis in the brain.
- Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519–523 (2011). et al.
- The human brain in a dish: the promise of iPSC-derived neurons. Cell 145, 831–834 (2011). , &
- The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat. Med. 16, 1210–1214 (2010).
- The problem of neuronal cell types: a physiological genomics approach. Trends Neurosci. 29, 339–345 (2006). , &
- New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 14, 202–216 (2013). et al.
- DSM-5 and RDoC: progress in psychiatry research? Nat. Rev. Neurosci. 14, 810–814 (2013). et al.
- Autism: many genes, common pathways? Cell 135, 391–395 (2008).
- Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167, 748–751 (2010). et al.
- Gene co-expression network topology provides a framework for molecular characterization of cellular state. Bioinformatics 20, 2242–2250 (2004). , , &
- Functional organization of the transcriptome in human brain. Nat. Neurosci. 11, 1271–1282 (2008). et al.
- Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013).
A study that constructs genome-wide co-expression networks to identify modules spanning prenatal human brain development and demonstrates how module structure can be validated with multiple data sources and how tissue-specific and temporally specific co-expression modules can provide new biological insights into genetic variants.
- Integrative approaches for finding modular structure in biological networks. Nat. Rev. Genet. 14, 719–732 (2013). , , &
- Genotype to phenotype via network analysis. Curr. Opin. Genet. Dev. 23, 611–621 (2013). , &
- Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).
This study identifies common transcriptomic changes in a heterogeneous neuropsychiatric disorder and illustrates how gene network modules can be validated experimentally and how network modules can be related to GWAS findings.
- Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc. Natl Acad. Sci. USA 103, 17402–17407 (2006). et al.
- The organization of the transcriptional network in specific neuronal classes. Mol. Syst. Biol. 5, 291 (2009). et al.
- Systematic survey reveals general applicability of 'guilt-by-association' within gene coexpression networks. BMC Bioinformatics 6, 227 (2005). , &
- PBK/TOPK, a proliferating neural progenitor-specific mitogen-activated protein kinase kinase. J. Neurosci. 25, 10773–10785 (2005). et al.
- Is my network module preserved and reproducible? PLoS Comput. Biol. 7, e1001057 (2011).
A description and comparison of multiple metrics for measuring modular structure in networks, which provides a statistical framework for demonstrating module preservation that is included in the R package WGCNA.[Au:OK?]
, , &
- A differential wiring analysis of expression data correctly identifies the gene containing the causal mutation. PLoS Comput. Biol. 5, e1000382 (2009). , &
- Differential coexpression analysis using microarray data and its application to human cancer. Bioinformatics 21, 4348–4355 (2005). , , &
- Comparison of co-expression measures: mutual information, correlation, and model based indices. BMC Bioinformatics 13, 328 (2012). , &
- Comparing statistical methods for constructing large scale gene networks. PLoS ONE 7, e29348 (2012).
This study compares multiple approaches for constructing large-scale gene networks, including methods based on correlation and mutual information.
, , , &
- Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. Bioinformatics http://dx.doi.org/10.1093/bioinformatics/btv118 (2015).
An evaluation of sample size and power for constructing co-expression networks with RNA-seq.
- Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders. Genes Brain Behav. 13, 13–24 (2013). , , , &
- A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4,17 (2005).
This paper describes the value of weighted co-expression networks over binary co-expression networks and discusses the theory behind the widely used WGCNA package.
- A map of human protein interactions derived from co-expression of human mRNAs and their orthologs. Mol. Syst. Biol. 4, 180 (2008). et al.
- Understanding network concepts in modules. BMC Syst. Biol. 1, 24 (2007). &
- ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinformatics 7, S7 (2006). et al.
- Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways. Sci. Signal. 4, ra65 (2011). et al.
- STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics 7, 191 (2006). &
- TimeDelay-ARACNE: reverse engineering of gene networks from time-course data by an information theoretic approach. BMC Bioinformatics 11, 154 (2010). , &
- Wisdom of crowds for robust gene network inference. Nat. Methods 9, 796–804 (2012).
This paper, from the DREAM challenge on regulatory network reconstruction, describes the results of applying multiple regulatory network inference algorithms to three large data sets from bacteria and yeast.
- Gene Ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000). et al.
- KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 27, 29–34 (1999). et al.
- Protein–protein interaction networks and biology — what's the connection? Nat. Biotechnol. 26, 69–72 (2008). , , &
- How complete are current yeast and human protein-interaction networks? Genome Biol. 7, 120 (2006). , &
- Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics. Nat. Methods 11, 868–874 (2014).
This study experimentally defines PPIs specific to cardiac tissue for four genes known to cause long QT syndrome and demonstrates how tissue-relevant PPI networks can be used to prioritize genetic association signals.
- Mass-spectrometry-based draft of the human proteome. Nature 509, 582–587 (2014). et al.
- A draft map of the human proteome. Nature 509, 575–581 (2014). et al.
- The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat. Commun. 6, 6404 (2015). et al.
- MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
- Assessing computational tools for the discovery of transcription factor binding sites. Nat. Biotechnol. 23, 137–144 (2005). et al.
- Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013). , , , &
- Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Res. 21, 447–455 (2011). et al.
- Genetics of intellectual disability. Curr. Opin. Genet. Dev. 18, 241–250 (2008).
- Genetic and epigenetic networks in intellectual disabilities. Annu. Rev. Genet. 45, 81–104 (2011).
- Intellectual disability and its relationship to autism spectrum disorders. Res. Dev. Disabil. 30, 1107–1114 (2009). &
- Fragile X and X-linked intellectual disability: four decades of discovery. Am. J. Hum. Genet. 90, 579–590 (2012). , &
- Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012). et al.
- Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012). et al.
- Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014). et al.
- Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27–29 (2003). et al.
- De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). et al.
- Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). et al.
- De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012). et al.
- Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). et al.
- Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9, 341–355 (2008). &
- Genetics of autism spectrum disorders. Trends Cogn. Sci. 15, 409–416 (2011).
- The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014). et al.
- Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014). et al.
- Epi4K Consortium & Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).
- Epilepsy genetics — past, present, and future. Curr. Opin. Genet. Dev. 21, 325–332 (2011). &
- De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). et al.
- A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). et al.
- Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat. Genet. 43, 864–868 (2011). et al.
- One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat. Neurosci. 17, 773–781 (2014). , , &
- Cross-Disorder, Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).
- Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice. Genome Med. 6, 29 (2014). &
- Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat. Neurosci. 17, 764–772 (2014). , &
- A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014). et al.
- Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).
- Robustness: mechanisms and consequences. Trends Genet. 25, 395–403 (2009).
This paper discusses the concept of canalization and its implications for molecular biology and evolution.
- Chromatin regulators, phenotypic robustness, and autism risk. Front. Genet. 5, 81 (2014). , &
- Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 22, 229–237 (2012). &
- Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57, 1618–1628 (2001). , , , &
- Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol. Dis. 30, 303–311 (2008). et al.
- Brain transcriptional and epigenetic associations with autism. PLoS ONE 7, e44736 (2012). , , , &
- Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genet. 8, e1002592 (2012). et al.
- Eigengene networks for studying the relationships between co-expression modules. BMC Syst. Biol. 1, 54 (2007). &
- Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014). et al.
- Schizophrenia. Lancet 374, 635–645 (2009). &
- Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660–669 (1987).
- Progress in the use of microarray technology to study the neurobiology of disease. Nat. Neurosci. 7, 434–439 (2004). &
- Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53–67 (2000). , , , &
- Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol. Psychiatry 13, 147–161 (2007). et al.
- Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc. Natl Acad. Sci. USA 98, 4746–4751 (2001). et al.
- Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol. Psychiatry 58, 85–96 (2005). et al.
- Synaptic changes in the brain of subjects with schizophrenia. Int. J. Dev. Neurosci. 29, 305–309 (2011). &
- Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol. Psychiatry 62, 711–721 (2007). , , , &
- Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Genome Res. 20, 403–412 (2010).
This work applies mutual information-based co-expression network analysis to transcriptomic data from post-mortem brains of individuals with schizophrenia to identify several schizophrenia-associated modules.
, , &
- Two gene co-expression modules differentiate psychotics and controls. Mol. Psychiatry 18, 1308–1314 (2012). et al.
- Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet. 8, e1002556 (2012). &
- From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14, 347–359 (2013). , &
- AutDB: a gene reference resource for autism research. Nucleic Acids Res. 37, D832–D836 (2009). , &
- Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013). et al.
- A quantitative framework to evaluate modeling of cortical development by neural stem cells. Neuron 83, 69–86 (2014). et al.
- The roles of FMRP-regulated genes in autism spectrum disorder: single- and multiple-hit genetic etiologies. Am. J. Hum. Genet. 93, 825–839 (2013). &
- Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518–529 (2013). et al.
- FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011). et al.
- The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15, 133–141 (2014). , , &
- CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc. Natl Acad. Sci. USA 111, E4468–E4477 (2014). et al.
- Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149, 525–537 (2012). et al.
- Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012). et al.
- Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263–276 (2014). et al.
- Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol. Psychiatry 18, 1054–1056 (2012). &
- Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Mol. Syst. Biol. 10, 774–774 (2014). et al.
- Protein interactome reveals converging molecular pathways among autism disorders. Sci. Transl Med. 3, 86ra49 (2011). et al.
- Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat. Commun. 5, 3650 (2014).
This study rigorously identifies the interactors of proteins encoded by autism candidate genes using brain-relevant isoforms and identifies interactions among CNV-affected genes.
- Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol. Cell 46, 884–892 (2012). et al.
- Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70, 898–907 (2011).
This study applies a rigorous framework to integrate multiple levels of molecular data and evaluates whether genes affected by CNV in autism were functionally interconnected.
- A single gene network accurately predicts phenotypic effects of gene perturbation in Caenorhabditis elegans. Nat. Genet. 40, 181–188 (2008). et al.
- Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886–897 (2011). et al.
- Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. PLoS Genet. 9, e1003523 (2013). et al.
- Diverse types of genetic variation converge on functional gene networks involved in schizophrenia. Nat. Neurosci. 15, 1723–1728 (2012). et al.
- Genotype to phenotype relationships in autism spectrum disorders. Nat. Neurosci. 18, 191–198 (2015). , , , &
- The discovery of integrated gene networks for autism and related disorders. Genome Res. 25, 142–154 (2015).
This study uses a network analysis method that combines gene co-expression and PPIs to identify modules that are highly interconnected in the network but that are also more likely to be mutated in individuals with neurodevelopmental disorders compared with controls.
, , &
- Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002).
- Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42–52 (2009). , , , &
- Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 73, 1216–1227 (2012). , , , &
- Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat. Med. 10, 1055–1063 (2004). , &
- A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron 51, 549–560 (2006). et al.
- Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum. Mol. Genet. 17, 1349–1362 (2008). et al.
- Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc. Natl Acad. Sci. USA 101, 2173–2178 (2004). et al.
- Genes and pathways underlying regional and cell type changes in Alzheimer's disease. Genome Med. 5, 48 (2013). , , , &
- Population-specific expression analysis (PSEA) reveals molecular changes in diseased brain. Nat. Methods 8, 945–947 (2011). , , , &
- 611–643 (Springer, 2010). & in Systems Biology for Signaling Networks (ed. Choi, S.) Ch. 25
- Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc. Natl Acad. Sci. USA 105, 4441–4446 (2008). et al.
- Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann. Neurol. 58, 909–919 (2005). et al.
- Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation. Proc. Natl Acad. Sci. USA 105, 7327–7332 (2008). et al.
- Genetic control of human brain transcript expression in Alzheimer disease. Am. J. Hum. Genet. 84, 445–458 (2009). et al.
- Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set. Physiol. Genomics 33, 240–256 (2008). et al.
- Systems level analysis of transcriptional changes in Alzheimer's disease and normal aging. J. Neurosci. 28, 1410–1420 (2008). , &
- Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc. Natl Acad. Sci. USA 107, 12698–12703 (2010). , &
- Variations in the transcriptome of Alzheimer's disease reveal molecular networks involved in cardiovascular diseases. Genome Biol. 9, R148 (2008). , &
- Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol. Aging 34, 2699–2714 (2013). et al.
- Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71, 1030–1042 (2011). et al.
- Endogenous Wnt signaling maintains neural progenitor cell potency. Stem Cells 27, 1130–1141 (2009). , , , &
- MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J. Biol. Chem. 289, 5184–5198 (2014). , &
- Alteration of the microRNA network during the progression of Alzheimer's disease. EMBO Mol. Med. 5, 1613–1634 (2013). et al.
- MicroRNA networks surrounding APP and amyloid-β metabolism — implications for Alzheimer's disease. Exp. Neurol. 235, 447–454 (2012). , , &
- Single-cell gene expression analysis: implications for neurodegenerative and neuropsychiatric disorders. Neurochem. Res. 29, 1053–1064 (2004). et al.
- FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains. Nat. Neurosci. 9, 443–452 (2006). , , , &
- Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135, 749–762 (2008). et al.
- A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003). et al.
- An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
An RNA-seq database of gene expression and splicing differences between major cell types in the mouse CNS that provides cell type-specific profiles that can be used to query cell type specificity in other studies.
- A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008). et al.
- A protein–protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801–814 (2006). et al.
- Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713–718 (2008). et al.
- A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Mol. Cell 15, 853–865 (2004). et al.
- Network organization of the Huntingtin proteomic interactome in mammalian brain. Neuron 75, 41–57 (2012).
Illustrates the power of network analysis for defining protein interaction modules across brain regions and time points to understand the huntingtin interactome.
- Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell 159, 402–414 (2014). et al.
- Systems genetics approaches to understand complex traits. Nat. Rev. Genet. 15, 34–48 (2013). &
- Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013).
This study combined network analysis in post-mortem tissue, eQTL mapping and Bayesian causal inference to identify a causal role for the gene TYROBP in Alzheimer disease.
- Using genetic markers to orient the edges in quantitative trait networks: the NEO software. BMC Syst. Biol. 2, 34 (2008). , , &
- Statistical power and significance testing in large-scale genetic studies. Nat. Rev. Genet. 15, 335–346 (2014). &
- Calculating sample size estimates for RNA sequencing data. J. Comput. Biol. 20, 970–978 (2013). , , , &
- Efficient experimental design and analysis strategies for the detection of differential expression using RNA-sequencing. BMC Genomics 13, 484 (2012). et al.
- Comprehensive evaluation of differential gene expression analysis methods for RNA-seq data. Genome Biol. 14, R95 (2013). et al.
- Power analysis and sample size estimation for RNA-seq differential expression. RNA 20, 1684–1696 (2014). , &
- Sequencing technology does not eliminate biological variability. Nat. Biotechnol. 29, 572–573 (2011). , , &
- Tackling the widespread and critical impact of batch effects in high-throughput data. Nat. Rev. Genet. 11, 733–739 (2010).
A must-read paper prior to pursuing the design or analysis of a high-throughput experiment, it contains advice and analyses for evaluating the contribution of technical and biological variation in data sets.
- Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies. J. Neurochem. 120, 473–473 (2011). et al.
- Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories. Nat. Biotechnol. 31, 1015–1022 (2013). , &
- Normalizing RNA-sequencing data by modeling hidden covariates with prior knowledge. PLoS ONE 8, e68141 (2013).
This study presents a comprehensive framework for thinking about signal and noise in gene expression data and unifies most known methods into one framework.
- 2013). , , & An Introduction to Statistical Learning (Springer Science & Business Media,
- Pathway-based approaches for analysis of genomewide association studies. Am. J. Hum. Genet. 81, 1278–1283 (2007). , &
- Bias towards large genes in autism. Nature 512, E1–E2 (2014). &
- Gene set analysis of genome-wide association studies: methodological issues and perspectives. Genomics 98, 1–8 (2011). , , , &
- Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 6, e1001097 (2010). et al.
- LRpath: a logistic regression approach for identifying enriched biological groups in gene expression data. Bioinformatics 25, 211–217 (2009). , &
- Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014). et al.
- Genomic perspectives of transcriptional regulation in forebrain development. Neuron 85, 27–47 (2015). , , &
- Analytical tools and current challenges in the modern era of neuroepigenomics. Nat. Neurosci. 17, 1476–1490 (2014). et al.
- Bayés, À. et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat. Neurosci. 14, 19–21 (2010).
- Bayés, À. et al. Comparative study of human and mouse postsynaptic proteomes finds high compositional conservation and abundance differences for key synaptic proteins. PLoS ONE 7, e46683 (2012).
- Applications of Connectivity Map in drug discovery and development. Drug Discov. Today 17, 1289–1298 (2012). &
- The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006).
- Creation and implications of a phenome-genome network. Nat. Biotechnol. 24, 55–62 (2006). &
- A nondegenerate code of deleterious variants in mendelian loci contributes to complex disease risk. Cell 155, 70–80 (2013). et al.
- Probing genetic overlap among complex human phenotypes. Proc. Natl Acad. Sci. USA 104, 11694–11699 (2007). , , &
- The Human Phenome Project. Nat. Genet. 34, 15–21 (2003). &
- Neurocognitive phenotypes and genetic dissection of disorders of brain and behavior. Neuron 68, 218–230 (2010). , &
- Technology Insight: querying the genome with microarrays — progress and hope for neurological disease. Nat. Clin. Pract. Neurol. 2, 147–158 (2006). &
- Developmental regulation of human cortex transcription and its clinical relevance at single base resolution. Nat. Neurosci. 18, 154–161 (2015). et al.
- The disruption of Celf6, a gene identified by translational profiling of serotonergic neurons, results in autism-related behaviors. J. Neurosci. 33, 2732–2753 (2013). et al.
- Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders. J. Neurosci. 34, 1420–1431 (2014). , , , &
- Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia. Proc. Natl Acad. Sci. USA 111, 4578–4583 (2014). et al.
- Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation. Genes Dev. 27, 565–578 (2013). et al.
- Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347, 1138–1142 (2015).
The first single-cell RNA-seq study of the adult mouse cortex and hippocampus that uses unsupervised clustering to identify dozens of cell types, including many distinct interneuron subtypes.
- Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex. Nat. Biotechnol. 32, 1053–1058 (2014). et al.
- Transcriptome in vivo analysis (TIVA) of spatially defined single cells in live tissue. Nat. Methods 11, 190–196 (2014). et al.
- Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013). &
- Molecular characterization of the dendritic growth cone: regulated mRNA transport and local protein synthesis. Neuron 17, 1173–1187 (1996). &
- Spatially restricting gene expression by local translation at synapses. Trends Neurosci. 33, 173–182 (2010). , &
- 418–429 (World Scientific, 2000). & in Pacific Symposiumon Biocomputing 2000 (eds Altman, R. B. et al.)
- 2011). Weighted Network Analysis: Applications in Genomics and Systems Biology (Springer,
- Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 7, e1001273 (2011). et al.
- Effects of functional bias on supervised learning of a gene network model. Methods Mol. Biol. 541, 463–475 (2009). &
- Statistical design and analysis of RNA sequencing data. Genetics 185, 405–416 (2010). &
- Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 3, e161 (2007). &
- Multi-platform assessment of transcriptome profiling using RNA-seq in the ABRF next-generation sequencing study. Nat. Biotechnol. 32, 915–925 (2014).
A comprehensive evaluation of different sequencing platforms and methodologies that identifies optimal parameters for RNA-seq, including for degraded RNA.
- RNA-seq differential expression studies: more sequence or more replication? Bioinformatics 30, 301–304 (2014).
A comparison of multiple RNA-seq differential expression methodologies that demonstrated biological replicates are more important than technical replicates and provided guidelines on sequencing depth.
- A comparison of methods for differential expression analysis of RNA-seq data. BMC Bioinformatics 14, 91 (2013). &
- Microarray data analysis: from disarray to consolidation and consensus. Nat. Rev. Genet. 7, 55–65 (2006). , , &
- A simple method for assessing sample sizes in microarray experiments. BMC Bioinformatics 7, 106 (2006).
- When is hub gene selection better than standard meta-analysis? PLoS ONE 8, e61505 (2013). , &
- 2010). Permutation, Parametric, and Bootstrap Tests of Hypotheses (Springer,
- Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res. 1239, 235–248 (2008). et al.
- Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease. Neurobiol.Aging 34, 1653–1661 (2013). et al.
- GO-Elite: a flexible solution for pathway and ontology over-representation. Bioinformatics 28, 2209–2210 (2012). et al.
- Supplementary information S1 (box) (1.42 MB)
Methodology and analysis for cross-disorder transcriptomic analysis.