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Connecting gene regulatory relationships to neurobiological mechanisms of brain disorders

Nancy Y. A Sey, Harper Fauni, Won Ma, Hyejung Won
doi: https://doi.org/10.1101/681353
Nancy Y. A Sey
UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
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Harper Fauni
UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
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Won Ma
UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
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Hyejung Won
UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
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  • For correspondence: hyejung_won@med.unc.edu
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Abstract

Despite being clinically distinguishable, many neuropsychiatric disorders display a remarked level of genetic correlation and overlapping symptoms. Deciphering neurobiological mechanisms underlying potential shared genetic etiology is challenging because (1) most common risk variants reside in the non-coding region of the genome, and (2) a genome-wide framework is required to compare genome-wide association studies (GWAS) having different power. To address these challenges, we developed a platform, Hi-C coupled MAGMA (H-MAGMA), that converts SNP-level summary statistics into gene-level association statistics by assigning non-coding SNPs to their cognate genes based on chromatin interactions. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows, and cell types implicated for each disorder. We found that neuropsychiatric disorder-associated genes coalesce at the level of developmental windows (mid-gestation) and cell-type specificity (excitatory neurons). On the contrary, neurodegenerative disorder-associated genes show more diverse cell type specific, and increasing expression over time, consistent with the age-associated elevated risk of developing neurodegenerative disorders. Genes associated with Alzheimer’s disease were not only highly expressed in microglia, but also subject to microglia and oligodendrocyte-specific dysregulation, highlighting the importance of understanding the cellular context in which risk variants exert their effects. We also obtained a set of pleiotropic genes that are shared across multiple psychiatric disorders and may form the basis for common neurobiological susceptibility. Pleiotropic genes are associated with neural activity and gene regulation, with selective expression in corticothalamic projection neurons. These results show how H-MAGMA adds to existing frameworks to help identify the neurobiological basis of shared and distinct genetic architecture of brain disorders.

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  • https://github.com/thewonlab/H-MAGMA

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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 4.0 International license.
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Posted June 24, 2019.
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Connecting gene regulatory relationships to neurobiological mechanisms of brain disorders
Nancy Y. A Sey, Harper Fauni, Won Ma, Hyejung Won
bioRxiv 681353; doi: https://doi.org/10.1101/681353
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Connecting gene regulatory relationships to neurobiological mechanisms of brain disorders
Nancy Y. A Sey, Harper Fauni, Won Ma, Hyejung Won
bioRxiv 681353; doi: https://doi.org/10.1101/681353

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