Bridging psychology and genetics using large-scale spatial analysis of neuroimaging and neurogenetic data

Understanding how microscopic molecules give rise to complex cognitive processes is a major goal of the biological sciences. The countless hypothetical molecule-cognition relationships necessitate discovery-based techniques to guide scientists toward the most productive lines of investigation. To this end, we present a novel discovery tool that uses spatial patterns of neural gene expression from the Allen Brain Institute (ABI) and large-scale functional neuroimaging meta-analyses from the Neurosynth framework to bridge neurogenetic and neuroimaging data. We quantified the spatial similarity between over 20,000 genes from the ABI and 48 psychological topics derived from lexical analysis of neuroimaging articles, producing a comprehensive set of gene/cognition mappings that we term the Neurosynth-gene atlas. We demonstrate the ability to independently replicate known gene/cognition associations (e.g., between dopamine and reward), and subsequently use it to identify a range of novel associations between individual molecules or genes and complex psychological phenomena such as reward, memory and emotion. Our results complement existing discovery-based methods such as GWAS, and provide a novel means of generating hypotheses about the neurogenetic substrates of complex cognitive functions.

[1]  C. Lorson,et al.  A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Stetak,et al.  Forgetting Is Regulated via Musashi-Mediated Translational Control of the Arp2/3 Complex , 2014, Cell.

[3]  Bruce S. McEwen,et al.  Quantitative densitometry of neurotransmitter receptors , 1982, Journal of Neuroscience Methods.

[4]  Blair T. Johnson,et al.  Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration , 2008, PLoS medicine.

[5]  Philip Seeman,et al.  Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine , 1991, Nature.

[6]  R. DeRubeis,et al.  Antidepressant drug effects and depression severity: a patient-level meta-analysis. , 2010, JAMA.

[7]  Allan R. Jones,et al.  The Allen Human Brain Atlas Comprehensive gene expression mapping of the human brain , 2012, Trends in Neurosciences.

[8]  M E Phelps,et al.  Positron emission tomography provides molecular imaging of biological processes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. Rabinovich,et al.  Galectins: regulators of acute and chronic inflammation , 2010, Annals of the New York Academy of Sciences.

[10]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[11]  Martin A. Lindquist,et al.  Evaluating the consistency and specificity of neuroimaging data using meta-analysis , 2009, NeuroImage.

[12]  Daniel H. Geschwind,et al.  Neuroscience in the era of functional genomics and systems biology , 2009, Nature.

[13]  F. Gage,et al.  New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? , 2010, Nature Reviews Neuroscience.

[14]  J. Melki,et al.  The role of the SMN gene in proximal spinal muscular atrophy. , 1998, Human molecular genetics.

[15]  M. Corbetta,et al.  Control of goal-directed and stimulus-driven attention in the brain , 2002, Nature Reviews Neuroscience.

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

[17]  S. Woods,et al.  A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan , 2003, Molecular Psychiatry.

[18]  A. Arnsten,et al.  Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions , 2004, Biological Psychiatry.

[19]  R. Poldrack Can cognitive processes be inferred from neuroimaging data? , 2006, Trends in Cognitive Sciences.

[20]  Rebecca Saxe,et al.  Contributions of episodic retrieval and mentalizing to autobiographical thought: Evidence from functional neuroimaging, resting-state connectivity, and fMRI meta-analyses , 2014, NeuroImage.

[21]  J S Fowler,et al.  PET evaluation of the dopamine system of the human brain. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  J. Delgado-García,et al.  Adenosine A2A Receptor Modulation of Hippocampal CA3-CA1 Synapse Plasticity During Associative Learning in Behaving Mice , 2009, Neuropsychopharmacology.

[23]  Rupert Lanzenberger,et al.  Meta-analysis of molecular imaging of serotonin transporters in major depression , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[24]  Somatostatin in the Pontine Reticular Formation Modulates Fear Potentiation of the Acoustic Startle Response: An Anatomical, Electrophysiological, and Behavioral Study , 1996, The Journal of Neuroscience.

[25]  G. Burnstock Purinergic signalling and disorders of the central nervous system , 2008, Nature Reviews Drug Discovery.

[26]  G. Rabinovich,et al.  Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. , 2012, Immunity.

[27]  E. Eichler,et al.  Regional patterns of gene expression in human and chimpanzee brains. , 2004, Genome research.

[28]  J. O'Doherty,et al.  Reward representations and reward-related learning in the human brain: insights from neuroimaging , 2004, Current Opinion in Neurobiology.

[29]  Terri L. Gilbert,et al.  The Human Brain Online: An Open Resource for Advancing Brain Research , 2012, PLoS biology.

[30]  J. Feldon,et al.  Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning. , 2011, Learning & memory.

[31]  John Morris,et al.  Multi-scale correlation structure of gene expression in the brain , 2011, Neural Networks.

[32]  T. Wienker,et al.  Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. , 2002, American journal of human genetics.

[33]  Russell A. Poldrack,et al.  Discovering Relations Between Mind, Brain, and Mental Disorders Using Topic Mapping , 2012, PLoS Comput. Biol..

[34]  A. Syrota,et al.  In Vivo Detection of Striatal Dopamine Release during Reward: A PET Study with [11C]Raclopride and a Single Dynamic Scan Approach , 2002, NeuroImage.

[35]  H. Yin,et al.  Genetic Deletion of A2A Adenosine Receptors in the Striatum Selectively Impairs Habit Formation , 2009, The Journal of Neuroscience.

[36]  H. Heinze,et al.  Mesolimbic Functional Magnetic Resonance Imaging Activations during Reward Anticipation Correlate with Reward-Related Ventral Striatal Dopamine Release , 2008, The Journal of Neuroscience.

[37]  M. Kress,et al.  Therapeutic targeting of the ceramide-to-sphingosine 1-phosphate pathway in pain. , 2013, Trends in pharmacological sciences.

[38]  P. Mckinnon Maintaining genome stability in the nervous system , 2013, Nature Neuroscience.

[39]  H. Horie,et al.  A role for galectin-1 in the immune response to peripheral nerve injury , 2009, Experimental Neurology.

[40]  R. Nesse,et al.  Treatment of Panic-Like Attacks with a Long-Acting Analogue of Somatostatin , 1990, Journal of Clinical Psychopharmacology.

[41]  R. Cabeza,et al.  Functional neuroimaging of autobiographical memory , 2007, Trends in Cognitive Sciences.

[42]  Luke J. Chang,et al.  Decoding the role of the insula in human cognition: functional parcellation and large-scale reverse inference. , 2013, Cerebral cortex.

[43]  Junjie Chen,et al.  Human Claspin Is Required for Replication Checkpoint Control* , 2003, Journal of Biological Chemistry.

[44]  R. Wise,et al.  Brain dopamine and reward. , 1989, Annual review of psychology.

[45]  R. Lamprecht The actin cytoskeleton in memory formation , 2014, Progress in Neurobiology.

[46]  Russell A. Poldrack,et al.  Large-scale automated synthesis of human functional neuroimaging data , 2011, Nature Methods.

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

[48]  Samuel M. McClure,et al.  BOLD Responses Reflecting Dopaminergic Signals in the Human Ventral Tegmental Area , 2008, Science.

[49]  Linda B. Buck,et al.  A second class of chemosensory receptors in the olfactory epithelium , 2006, Nature.

[50]  J. Palacios,et al.  Visualization of dopamine D1, D2 and D3 receptor mRNA's in human and rat brain , 1992, Neurochemistry International.

[51]  R. Weinberg,et al.  Disruption of Arp2/3 Results in Asymmetric Structural Plasticity of Dendritic Spines and Progressive Synaptic and Behavioral Abnormalities , 2013, The Journal of Neuroscience.

[52]  Rene Hen,et al.  Young and excitable: the function of new neurons in the adult mammalian brain , 2005, Current Opinion in Neurobiology.

[53]  Yong Li,et al.  Relationship between learning and memory deficits and Arp2 expression in the hippocampus in rats with traumatic brain injury. , 2012, World neurosurgery.