Journal
NATURE GENETICS
Volume 53, Issue 2, Pages 166-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-00761-3
Keywords
-
Categories
Funding
- National Institutes of Health [R01HG005998, U54HL117798, R01GM071966]
- U.S. Department of Health and Human Services [HHSN272201000054C]
- Simons Foundation [395506]
- Princeton Institute for Computational Science and Engineering
- Princeton University Office of Information Technology's Research Computing department
Ask authors/readers for more resources
The research revealed the crucial role of RNA-binding proteins (RBPs) in psychiatric disorder risk, with the pathogenic contribution of noncoding variants impacting RBP target sites being a key factor. RBP dysregulation explains a significant amount of heritability not captured by large-scale studies and has a stronger impact.
Despite the strong genetic basis of psychiatric disorders, the underlying molecular mechanisms are largely unmapped. RNA-binding proteins (RBPs) are responsible for most post-transcriptional regulation, from splicing to translation to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. However, quantifying the pathogenic contribution of noncoding variants impacting RBP target sites is challenging. Here, we leverage a deep learning approach that can accurately predict the RBP target site dysregulation effects of mutations and discover that RBP dysregulation is a principal contributor to psychiatric disorder risk. RBP dysregulation explains a substantial amount of heritability not captured by large-scale molecular quantitative trait loci studies and has a stronger impact than common coding region variants. We share the genome-wide profiles of RBP dysregulation, which we use to identify DDHD2 as a candidate schizophrenia risk gene. This resource provides a new analytical framework to connect the full range of RNA regulation to complex disease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available