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

TitleGenome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk.
Publication TypeJournal Article
Year of Publication2021
AuthorsPark, CY, Zhou, J, Wong, AK, Chen, KM, Theesfeld, CL, Darnell, RB, Troyanskaya, OG
JournalNat Genet
Date Published2021 Feb
Keywords3' Untranslated Regions, Deep Learning, Gene Expression Regulation, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mental Disorders, Mutation, Nuclear Factor 90 Proteins, Peptide Elongation Factors, Phospholipases, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Ribonucleoprotein, U5 Small Nuclear, RNA Helicases, RNA Processing, Post-Transcriptional, RNA-Binding Proteins, Schizophrenia, Trans-Activators

<p>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.</p>

Alternate JournalNat Genet
PubMed ID33462483
PubMed Central IDPMC7886016
Grant ListHHSN272201000054C / AI / NIAID NIH HHS / United States
U54 HL117798 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R35 NS097404 / NS / NINDS NIH HHS / United States
R01 GM071966 / GM / NIGMS NIH HHS / United States
R01 HG005998 / HG / NHGRI NIH HHS / United States