AUTHOR=Su Xi , Li Wenqiang , Lv Luxian , Li Xiaoyan , Yang Jinfeng , Luo Xiong-Jian , Liu Jiewei 

TITLE=Transcriptome-Wide Association Study Provides Insights Into the Genetic Component of Gene Expression in Anxiety

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.740134

DOI=10.3389/fgene.2021.740134

ISSN=1664-8021

ABSTRACT=<p>Anxiety disorders are common mental disorders that often result in disability. Recently, large-scale genome-wide association studies (GWASs) have identified several novel risk variants and loci for anxiety disorders (or anxiety traits). Nevertheless, how the reported risk variants confer risk of anxiety remains unknown. To identify genes whose <italic>cis</italic>-regulated expression levels are associated with risk of anxiety traits, we conducted a transcriptome-wide association study (TWAS) by integrating genome-wide associations from a large-scale GWAS (<italic>N</italic> = 175,163) (which evaluated anxiety traits based on Generalized Anxiety Disorder 2-item scale (GAD-2) score) and brain expression quantitative trait loci (eQTL) data (from the PsychENCODE and GTEx). We identified 19 and 17 transcriptome-wide significant (TWS) genes in the PsychENCODE and GTEx, respectively. Intriguingly, 10 genes showed significant associations with anxiety in both datasets, strongly suggesting that genetic risk variants may confer risk of anxiety traits by regulating the expression of these genes. Top TWS genes included <italic>RNF123</italic>, <italic>KANSL1-AS1, GLYCTK, CRHR1, DND1P1, MAPT</italic> and <italic>ARHGAP27.</italic> Of note, 25 TWS genes were not implicated in the original GWAS. Our TWAS identified 26 risk genes whose <italic>cis</italic>-regulated expression were significantly associated with anxiety, providing important insights into the genetic component of gene expression in anxiety disorders/traits and new clues for future drug development.</p>