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

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.

SUBMITTER: Su X

PROVIDER: S-EPMC8505959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS:We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS:Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ?15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS:This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

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

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