Genome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk

Christopher Y. Park, Jian Zhou, Aaron K. Wong, Kathleen M. Chen, Chandra L. Theesfeld, Robert B. Darnell, Olga G. Troyanskaya

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)166-173
Number of pages8
JournalNature Genetics
Volume53
Issue number2
DOIs
StatePublished - Feb 2021

All Science Journal Classification (ASJC) codes

  • Genetics

Fingerprint

Dive into the research topics of 'Genome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk'. Together they form a unique fingerprint.

Cite this