Functional annotation of rare structural variation in the human brain
By
Michael E. Talkowski,
Xuefang Zhao,
Mary Lauren Benton,
Thaneer Perumal,
Ryan L. Collins,
Gabriel E. Hoffman,
Jessica S Johnson,
Laura Sloofman,
Harold Z Wang,
CommonMind Consortium,
Kristen J. Brennand,
Harrison Brand,
Solveig K. Sieberts,
Stefano Marenco,
Mette A. Peters,
Barbara K Lipska,
Panos Roussos,
John Anthony Capra,
Michael Talkowski,
Douglas M. Ruderfer
Posted 23 Jul 2019
bioRxiv DOI: 10.1101/711754
(published DOI: 10.1038/s41467-020-16736-1)
Structural variants (SVs) contribute substantially to risk of many brain related disorders including autism and schizophrenia. However, annotating the potential contribution of SVs to disease remains a major challenge. Here, we integrated high resolution SV calling from genome-sequencing in 755 human post-mortem brains with dorsal lateral prefrontal cortex RNA-sequencing from a subset of 629 samples to quantify the dosage and regulatory effects of SVs. We show that genic (p = 5.44×10−9) and regulatory SVs (enhancer p = 3.22×10−23, CTCF p = 3.86×10−18) are present at significantly lower frequencies than intergenic SVs after correcting for SV length. Copy number variants (CNVs)—deletions and duplications—exhibit a significant quantitative and directional relationship between the proportion of genic and regulatory content altered and gene expression, and the size of the effect is inversely correlated with the loss-of-function intolerance of the gene. We trained a joint linear model that leverages genic and regulatory annotations to predict expression effects of rare CNVs in independent samples (R2 = 0.21-0.41). We further developed a regulatory disruption score for each CNV that aggregates the predicted expression across all affected genes weighted by the genes’ intolerance score and applied it to an independent set of SVs from 14,891 genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders by ClinGen had significantly more extreme regulatory disruption scores than the rest of the SVs. Rank ordering based on the most extreme regulatory disruption scores prioritized pathogenic deletions that would not have been prioritized by frequency or length alone. This work points to the deleteriousness of regulatory SVs, particularly those altering CTCF sites. We further provide a simple approach for functionally annotating the regulatory effects of SVs in the human brain that has potential to be useful in larger SV studies and should improve as more regulatory annotation data is generated.
Download data
- Downloaded 1,199 times
- Download rankings, all-time:
- Site-wide: 15,054
- In genomics: 1,585
- Year to date:
- Site-wide: 37,483
- Since beginning of last month:
- Site-wide: 27,283
Altmetric data
Downloads over time
Distribution of downloads per paper, site-wide
PanLingua
News
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!