A practical guide to linking brain-wide gene expression and neuroimaging data

ABSTRACT The recent availability of comprehensive, brain‐wide gene expression atlases such as the Allen Human Brain Atlas (AHBA) has opened new opportunities for understanding how spatial variations on molecular scale relate to the macroscopic neuroimaging phenotypes. A rapidly growing body of literature is demonstrating relationships between gene expression and diverse properties of brain structure and function, but approaches for combining expression atlas data with neuroimaging are highly inconsistent, with substantial variations in how the expression data are processed. The degree to which these methodological variations affect findings is unclear. Here, we outline a seven‐step analysis pipeline for relating brain‐wide transcriptomic and neuroimaging data and compare how different processing choices influence the resulting data. We suggest that studies using the AHBA should work towards a unified data processing pipeline to ensure consistent and reproducible results in this burgeoning field.

[1]  Roman Jaksik,et al.  Microarray experiments and factors which affect their reliability , 2015, Biology Direct.

[2]  Allan R. Jones,et al.  Canonical Genetic Signatures of the Adult Human Brain , 2015, Nature Neuroscience.

[3]  Stanley J. Watson,et al.  Stress amplifies sex differences in primate prefrontal profiles of gene expression , 2017, Biology of Sex Differences.

[4]  E. Grigorenko,et al.  Age-related changes of gene expression in the neocortex: Preliminary data on RNA-Seq of the transcriptome in three functionally distinct cortical areas , 2012, Development and Psychopathology.

[5]  René S. Kahn,et al.  Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia , 2017, Biological Psychiatry.

[6]  Ben D. Fulcher,et al.  A transcriptional signature of hub connectivity in the mouse connectome , 2016, Proceedings of the National Academy of Sciences.

[7]  John Quackenbush Microarray data normalization and transformation , 2002, Nature Genetics.

[8]  Edsger W. Dijkstra,et al.  A note on two problems in connexion with graphs , 1959, Numerische Mathematik.

[9]  Jonathan D. Power,et al.  Recent progress and outstanding issues in motion correction in resting state fMRI , 2015, NeuroImage.

[10]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[11]  Marcel J. T. Reinders,et al.  Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington’s Disease , 2017, Front. Mol. Neurosci..

[12]  Ben D. Fulcher,et al.  An evaluation of the efficacy, reliability, and sensitivity of motion correction strategies for resting-state functional MRI , 2017, NeuroImage.

[13]  M. Selbach,et al.  Global quantification of mammalian gene expression control , 2011, Nature.

[14]  Peter Fonagy,et al.  Structural covariance networks are coupled to expression of genes enriched in supragranular layers of the human cortex , 2017, NeuroImage.

[15]  Yusuke Nakamura,et al.  Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease , 2009, Nature Genetics.

[16]  B. Futcher,et al.  A Sampling of the Yeast Proteome , 1999, Molecular and Cellular Biology.

[17]  Ayla Arslan,et al.  Genes, brains, and behavior: imaging genetics for neuropsychiatric disorders. , 2015, The Journal of neuropsychiatry and clinical neurosciences.

[18]  A. Raj,et al.  Spatial patterns of genome‐wide expression profiles reflect anatomic and fiber connectivity architecture of healthy human brain , 2014, Human brain mapping.

[19]  S. Cole,et al.  CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Social Regulation of Human Gene , 2022 .

[20]  Jan Barciszewski,et al.  Beyond the proteome: non-coding regulatory RNAs , 2002, Genome Biology.

[21]  Paul Pavlidis,et al.  Neuron-Enriched Gene Expression Patterns are Regionally Anti-Correlated with Oligodendrocyte-Enriched Patterns in the Adult Mouse and Human Brain , 2013, Front. Neurosci..

[22]  K. Dolinski,et al.  Use and misuse of the gene ontology annotations , 2008, Nature Reviews Genetics.

[23]  Adeel Razi,et al.  Brain Regions Showing White Matter Loss in Huntington’s Disease Are Enriched for Synaptic and Metabolic Genes , 2017, Biological Psychiatry.

[24]  Jason M Keil,et al.  Brain Transcriptome Databases: A User's Guide , 2018, The Journal of Neuroscience.

[25]  Leon French,et al.  A FreeSurfer view of the cortical transcriptome generated from the Allen Human Brain Atlas , 2015, Front. Neurosci..

[26]  Leopold Parts,et al.  Gene expression changes with age in skin, adipose tissue, blood and brain , 2013, Genome Biology.

[27]  Timothy O. Laumann,et al.  Sources and implications of whole-brain fMRI signals in humans , 2017, NeuroImage.

[28]  Sonja W. Scholz,et al.  Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease , 2009, Nature Genetics.

[29]  John D. Murray,et al.  Hierarchy of transcriptomic specialization across human cortex captured by myelin map topography , 2017, bioRxiv.

[30]  Michael Hawrylycz,et al.  Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. , 2014, Cell metabolism.

[31]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[32]  Andre Altmann,et al.  Re-Annotator: Annotation Pipeline for Microarray Probe Sequences , 2015, PloS one.

[33]  Christos Davatzikos,et al.  Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity , 2017, NeuroImage.

[34]  Carl W. Cotman,et al.  Gene expression changes in the course of normal brain aging are sexually dimorphic , 2008, Proceedings of the National Academy of Sciences.

[35]  Hongfang Liu,et al.  Microarray probes and probe sets. , 2010, Frontiers in bioscience.

[36]  M. Rietschel,et al.  Correlated gene expression supports synchronous activity in brain networks , 2015, Science.

[37]  Philipp Khaitovich,et al.  Aging and Gene Expression in the Primate Brain , 2005, PLoS biology.

[38]  Robert B. Innis,et al.  Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot , 2016, NeuroImage.

[39]  Sjoerd M. H. Huisman,et al.  Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas , 2016, Human Genetics.

[40]  Spiro P. Pantazatos,et al.  Commentary: BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks. Science 348, 1241-4 , 2016 .

[41]  J. Leek,et al.  Temporal dynamics and genetic control of transcription in the human prefrontal cortex , 2011, Nature.

[42]  Cedric E. Ginestet,et al.  Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson's disease and Progressive Supranuclear Palsy , 2016 .

[43]  Anders M. Dale,et al.  An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest , 2006, NeuroImage.

[44]  George E. Gantner,et al.  The Postmortem Interval , 1964 .

[45]  Ann M. Hess,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Filtering for increased power for microarray data analysis , 2008 .

[46]  Hervé Abdi,et al.  Differences in Human Cortical Gene Expression Match the Temporal Properties of Large-Scale Functional Networks , 2014, PloS one.

[47]  R. Ross,et al.  Brain pH has a significant impact on human postmortem hippocampal gene expression profiles , 2006, Brain Research.

[48]  Ence Yang,et al.  Systematic analysis of gene expression patterns associated with postmortem interval in human tissues , 2017, Scientific Reports.

[49]  Jianfeng Feng,et al.  The functional and genetic associations of neuroimaging data: a toolbox , 2017, bioRxiv.

[50]  Alan C. Evans,et al.  Gene networks show associations with seed region connectivity , 2017, Human brain mapping.

[51]  Fenna M. Krienen,et al.  Gene expression links functional networks across cortex and striatum , 2018, Nature Communications.

[52]  M. Gerstein,et al.  RNA-Seq: a revolutionary tool for transcriptomics , 2009, Nature Reviews Genetics.

[53]  Andreas Scherer,et al.  Batch Effects and Noise in Microarray Experiments: Sources and Solutions , 2009 .

[54]  Penelope Hartland-Thunberg Sources and Implications of the Global Debt Crisis , 1986 .

[55]  Peter B. Jones,et al.  Adolescent Tuning of Association Cortex in Human Structural Brain Networks , 2017, bioRxiv.

[56]  A. Komorowski,et al.  Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain , 2016, Cerebral cortex.

[57]  Andre Altmann,et al.  Re-Annotator: Annotation Pipeline for Microarrays , 2015, bioRxiv.

[58]  Daniel S. Margulies,et al.  NeuroVault.org: a web-based repository for collecting and sharing unthresholded statistical maps of the human brain , 2014, bioRxiv.

[59]  S. Drăghici,et al.  Analysis of microarray experiments of gene expression profiling. , 2006, American journal of obstetrics and gynecology.

[60]  A. Meyer-Lindenberg,et al.  Intermediate phenotypes and genetic mechanisms of psychiatric disorders , 2006, Nature Reviews Neuroscience.

[61]  C A Acevedo-Triana,et al.  Comparing the Expression of Genes Related to Serotonin (5-HT) in C57BL/6J Mice and Humans Based on Data Available at the Allen Mouse Brain Atlas and Allen Human Brain Atlas , 2017, Neurology research international.

[62]  Kimberly R. Kukurba,et al.  RNA Sequencing and Analysis. , 2015, Cold Spring Harbor protocols.

[63]  Anders M. Dale,et al.  Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia , 2017, Acta Neuropathologica.

[64]  Jonas Richiardi,et al.  Distance is not everything in imaging genomics of functional networks: reply to a commentary on Correlated gene expression supports synchronous activity in brain networks , 2017 .

[65]  Ben D. Fulcher,et al.  Hub connectivity, neuronal diversity, and gene expression in the Caenorhabditis elegans connectome , 2018, PLoS Comput. Biol..

[66]  Jan Gorodkin,et al.  Associating transcription factors and conserved RNA structures with gene regulation in the human brain , 2017, Scientific Reports.

[67]  Thomas E. Nichols,et al.  The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data , 2014, Brain Imaging and Behavior.

[68]  Kimberly Van Auken,et al.  WormBase: a comprehensive resource for nematode research , 2009, Nucleic Acids Res..

[69]  P. Expert,et al.  MENGA: A New Comprehensive Tool for the Integration of Neuroimaging Data and the Allen Human Brain Transcriptome Atlas , 2016, PloS one.

[70]  Louis Richer,et al.  Cell-Specific Gene-Expression Profiles and Cortical Thickness in the Human Brain , 2018, Cerebral cortex.

[71]  Ben D. Fulcher,et al.  Transcriptional signatures of connectomic subregions of the human striatum , 2016, bioRxiv.

[72]  Raghu Machiraju,et al.  An integrative analysis of regional gene expression profiles in the human brain. , 2015, Methods.

[73]  Max A. Little,et al.  Highly comparative time-series analysis: the empirical structure of time series and their methods , 2013, Journal of The Royal Society Interface.

[74]  Andrew J. Lees,et al.  Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy , 2011, Nature Genetics.

[75]  Yudong D. He,et al.  Effects of atmospheric ozone on microarray data quality. , 2003, Analytical chemistry.

[76]  Gal Chechik,et al.  On Expression Patterns and Developmental Origin of Human Brain Regions , 2016, PLoS Comput. Biol..

[77]  Murray Grossman,et al.  Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy , 2015, Nature Communications.

[78]  Wen J. Li,et al.  Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation , 2015, Nucleic Acids Res..

[79]  S. Gygi,et al.  Correlation between Protein and mRNA Abundance in Yeast , 1999, Molecular and Cellular Biology.

[80]  Chen Chu,et al.  Analysis of Gene Expression Profiles in the Human Brain Stem, Cerebellum and Cerebral Cortex , 2016, PloS one.

[81]  A. Ramasamy,et al.  Widespread sex differences in gene expression and splicing in the adult human brain , 2013, Nature Communications.

[82]  Peter B. Jones,et al.  Gene transcription profiles associated with inter-modular hubs and connection distance in human functional magnetic resonance imaging networks , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[83]  Michael Wagner,et al.  Systematic Spatial Bias in DNA Microarray Hybridization Is Caused by Probe Spot Position-Dependent Variability in Lateral Diffusion , 2011, PloS one.

[84]  Jesse Gillis,et al.  Gene function analysis in complex data sets using ErmineJ , 2010, Nature Protocols.

[85]  A. Hariri,et al.  Imaging genetics. , 2009, Journal of the American Academy of Child and Adolescent Psychiatry.

[86]  David M. Hockenbery,et al.  Hsp90 Inhibition Decreases Mitochondrial Protein Turnover , 2007, PloS one.

[87]  H. Barbas General cortical and special prefrontal connections: principles from structure to function. , 2015, Annual review of neuroscience.

[88]  Jesper Andersson,et al.  A multi-modal parcellation of human cerebral cortex , 2016, Nature.

[89]  Jocelyn E. Krebs,et al.  Lewin's Genes X , 2009 .

[90]  Allan R. Jones,et al.  An anatomically comprehensive atlas of the adult human brain transcriptome , 2012, Nature.

[91]  Mingfeng Li,et al.  Laminar and temporal expression dynamics of coding and noncoding RNAs in the mouse neocortex. , 2014, Cell reports.

[92]  Ed S Lein,et al.  Improving reliability and absolute quantification of human brain microarray data by filtering and scaling probes using RNA-Seq , 2014, BMC Genomics.

[93]  Allan R. Jones,et al.  Comprehensive transcriptional map of primate brain development , 2016, Nature.

[94]  Edward T. Bullmore,et al.  Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism , 2017, bioRxiv.

[95]  Ben D. Fulcher,et al.  Bridging the Gap between Connectome and Transcriptome , 2019, Trends in Cognitive Sciences.

[96]  Joshua T. Burdick,et al.  Common genetic variants account for differences in gene expression among ethnic groups , 2007, Nature Genetics.

[97]  F. A. Kolpakov,et al.  Gene networks , 2007, Molecular Biology.

[98]  Allissa Dillman,et al.  Age-associated changes in gene expression in human brain and isolated neurons , 2013, Neurobiology of Aging.

[99]  Daniel R. Salomon,et al.  Strategies for aggregating gene expression data: The collapseRows R function , 2011, BMC Bioinformatics.

[100]  J. Kleinman,et al.  Spatiotemporal transcriptome of the human brain , 2011, Nature.

[101]  M Takeda,et al.  Imaging Genetics and Psychiatric Disorders , 2015, Current molecular medicine.

[102]  Spiro P. Pantazatos,et al.  Commentary: BRAIN NETWORKS. Correlated Gene Expression Supports Synchronous Activity in Brain Networks. Science 348, 1241–4 , 2017, Front. Neurosci..

[103]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[104]  Siegfried Kasper,et al.  Spatial analysis and high resolution mapping of the human whole-brain transcriptome for integrative analysis in neuroimaging , 2018, NeuroImage.

[105]  Peter B. Jones,et al.  373. Adolescence is Associated with Genomically Patterned Consolidation of the Hubs of the Human Brain Connectome , 2016, Biological Psychiatry.

[106]  Douglas G. Walker,et al.  Postmortem interval effect on RNA and gene expression in human brain tissue , 2011, Cell and Tissue Banking.

[107]  A. Bernacchia,et al.  Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography , 2018, Nature Neuroscience.

[108]  D. Geschwind,et al.  Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis , 2009, Neuron.

[109]  C. Guda,et al.  Global gene expression profiling of healthy human brain and its application in studying neurological disorders , 2017, Scientific Reports.

[110]  Jung Kyoon Choi,et al.  Environmental Effects on Gene Expression Phenotype Have Regional Biases in the Human Genome , 2007, Genetics.

[111]  Fenna M. Krienen,et al.  Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain , 2016, Proceedings of the National Academy of Sciences.

[112]  Alexander Gerhard,et al.  Frontotemporal dementia and its subtypes: a genome-wide association study , 2014, The Lancet Neurology.

[113]  Allan R. Jones,et al.  Transcriptional Landscape of the Prenatal Human Brain , 2014, Nature.

[114]  M. Gerstein,et al.  Comparing protein abundance and mRNA expression levels on a genomic scale , 2003, Genome Biology.

[115]  Alex Fornito,et al.  Transcriptional signatures of connectomic subregions of the human striatum , 2016, bioRxiv.