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Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Jakob Seidlitz, Ajay Nadig, Siyuan Liu, Richard A.I. Bethlehem, Petra E. Vértes, Sarah E. Morgan, František Váša, Rafael Romero-Garcia, François M. Lalonde, Liv S. Clasen, Jonathan D. Blumenthal, Casey Paquola, Boris Bernhardt, Konrad Wagstyl, Damon Polioudakis, Luis de la Torre-Ubieta, Daniel H. Geschwind, Joan C. Han, Nancy R. Lee, Declan G. Murphy, Edward T. Bullmore, Armin Raznahan
doi: https://doi.org/10.1101/573279
Jakob Seidlitz
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
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  • For correspondence: jakob.seidlitz@nih.gov raznahana@mail.nih.gov
Ajay Nadig
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
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Siyuan Liu
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
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Richard A.I. Bethlehem
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
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Petra E. Vértes
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
cSchool of Mathematical Sciences, Queen Mary University of London, London, UK
dThe Alan Turing Institute, London, UK
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Sarah E. Morgan
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
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František Váša
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
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Rafael Romero-Garcia
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
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François M. Lalonde
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
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Liv S. Clasen
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
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Jonathan D. Blumenthal
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
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Casey Paquola
eMcConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, QC, Canada
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Boris Bernhardt
eMcConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, QC, Canada
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Konrad Wagstyl
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
fMcGill Centre for Integrative Neuroscience, McGill University, Montreal, QC, Canada
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Damon Polioudakis
gDepartment of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
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Luis de la Torre-Ubieta
gDepartment of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
hDepartment of Psychiatry and Biobehavioral Sciences, Semel Institute, David Geffen School of Medicine, UCLA, USA
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Daniel H. Geschwind
gDepartment of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
iDepartment of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
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Joan C. Han
jDepartments of Pediatrics and Physiology, University of Tennessee Health Science Center and Le Bonheur Children’s Foundation Research Institute, Memphis, TN, USA
kPediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD, USA
lUnit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
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Nancy R. Lee
mDrexel University, Department of Psychology, Philadelphia, PA, USA
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Declan G. Murphy
nKing’s College London, Institute of Psychiatry, London, UK
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Edward T. Bullmore
bUniversity of Cambridge, Department of Psychiatry, Cambridge, UK
oCambridgeshire and Peterborough NHS Foundation Trust, Huntingdon, UK
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Armin Raznahan
aDevelopmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, MD, USA
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  • For correspondence: jakob.seidlitz@nih.gov raznahana@mail.nih.gov
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Abstract

Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorder’s anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this “transcriptional vulnerability model” by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

Footnotes

  • Added new analyses/validations and additions to the main text based on comments from reviewers after a journal rejection

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 17, 2019.
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Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders
Jakob Seidlitz, Ajay Nadig, Siyuan Liu, Richard A.I. Bethlehem, Petra E. Vértes, Sarah E. Morgan, František Váša, Rafael Romero-Garcia, François M. Lalonde, Liv S. Clasen, Jonathan D. Blumenthal, Casey Paquola, Boris Bernhardt, Konrad Wagstyl, Damon Polioudakis, Luis de la Torre-Ubieta, Daniel H. Geschwind, Joan C. Han, Nancy R. Lee, Declan G. Murphy, Edward T. Bullmore, Armin Raznahan
bioRxiv 573279; doi: https://doi.org/10.1101/573279
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Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders
Jakob Seidlitz, Ajay Nadig, Siyuan Liu, Richard A.I. Bethlehem, Petra E. Vértes, Sarah E. Morgan, František Váša, Rafael Romero-Garcia, François M. Lalonde, Liv S. Clasen, Jonathan D. Blumenthal, Casey Paquola, Boris Bernhardt, Konrad Wagstyl, Damon Polioudakis, Luis de la Torre-Ubieta, Daniel H. Geschwind, Joan C. Han, Nancy R. Lee, Declan G. Murphy, Edward T. Bullmore, Armin Raznahan
bioRxiv 573279; doi: https://doi.org/10.1101/573279

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