Open AccessGenome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk
Author(s) -
Christopher Y. Park,
Jian Zhou,
Aaron K. Wong,
Kathleen M. Chen,
Chandra L. Theesfeld,
Robert B. Darnell,
Olga G. Troyanskaya
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-00761-3
Subject(s) - biology , rna binding protein , genome wide association study , genetics , rna splicing , expression quantitative trait loci , computational biology , quantitative trait locus , gene , rna , single nucleotide polymorphism , genotype
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.