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

Xi Su; Wenqiang Li; Luxian Lv; Xiaoyan Li; Jinfeng Yang; Xiong-Jian Luo; Jiewei Liu

doi:10.3389/fgene.2021.740134

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

Front Genet. 2021 Sep 28:12:740134. doi: 10.3389/fgene.2021.740134. eCollection 2021.

Authors

Xi Su^{1

2}, Wenqiang Li^{1

2}, Luxian Lv^{1

2}, Xiaoyan Li³, Jinfeng Yang^{3

4}, Xiong-Jian Luo^{3

4

5

6}, Jiewei Liu³

Affiliations

¹ Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
² Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
⁴ Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
⁵ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
⁶ KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.

Abstract

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 cis-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 (N = 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 RNF123, KANSL1-AS1, GLYCTK, CRHR1, DND1P1, MAPT and ARHGAP27. Of note, 25 TWS genes were not implicated in the original GWAS. Our TWAS identified 26 risk genes whose cis-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.

Keywords: GTEx; GWAS; PsychENCODE; TWAS; anxiety.