Functional annotation of rare structural variation in the human brain

Lide Han, Xuefang Zhao, Mary Lauren Benton, Thaneer Perumal, Ryan L. Collins, Gabriel E. Hoffman, Jessica S. Johnson, Laura Sloofman, Harold Z. Wang, Matthew R. Stone, Kristen J. Brennand, Harrison Brand, Solveig K. Sieberts, Stefano Marenco, Mette A. Peters, Barbara K. Lipska, Panos Roussos, John A. Capra, Michael Talkowski and Douglas M. Ruderfer ()
Additional contact information
Lide Han: Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center
Xuefang Zhao: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (M.I.T.)
Mary Lauren Benton: Vanderbilt Genetics Institute, Vanderbilt University Medical Center
Thaneer Perumal: Sage Bionetworks
Ryan L. Collins: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (M.I.T.)
Gabriel E. Hoffman: Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai
Jessica S. Johnson: Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai
Laura Sloofman: Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai
Harold Z. Wang: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (M.I.T.)
Matthew R. Stone: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (M.I.T.)
Kristen J. Brennand: Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai
Harrison Brand: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (M.I.T.)
Solveig K. Sieberts: Sage Bionetworks
Stefano Marenco: Human Brain Collection Core, Intramural Research Program, NIMH, National Institutes of Health
Mette A. Peters: Sage Bionetworks
Barbara K. Lipska: Human Brain Collection Core, Intramural Research Program, NIMH, National Institutes of Health
Panos Roussos: Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai
John A. Capra: Vanderbilt Genetics Institute, Vanderbilt University Medical Center
Michael Talkowski: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (M.I.T.)
Douglas M. Ruderfer: Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs.

Date: 2020
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DOI: 10.1038/s41467-020-16736-1

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