Genome-wide insights into generalised anxiety using a dimensional symptom severity approach

Area of Science:

• Genetics
• Psychiatry
• Epidemiology

Background:

• Generalized anxiety disorder is a common mental health condition with a significant genetic component.
• Understanding the genetic architecture of anxiety is crucial for developing effective treatments.

Purpose of the Study:

• To conduct a large-scale genome-wide association meta-analysis to identify genetic variants associated with generalized anxiety symptom severity.
• To explore the genetic correlations between anxiety and other mental and physical health traits.

Main Methods:

• Genome-wide association meta-analysis of generalized anxiety symptom severity in 696,563 individuals of European ancestry from 14 cohorts.
• Identification of genome-wide significant variants and loci.
• Calculation of SNP-based heritability.
• Polygenic score analysis across diverse ancestry groups.
• Estimation of genetic correlations with various health traits.
• Gene-based and pathway analyses.

Main Results:

• Identified 82 independent genome-wide significant variants within 76 loci, with 41 novel for anxiety.
• SNP-based heritability of anxiety symptom severity was estimated at 5.9%.
• Polygenic scores showed significant associations with anxiety symptom severity and disorder across European, African, and South Asian ancestry samples.
• Significant genetic correlations were found with neuroticism, depression, irritable bowel syndrome, coronary artery disease, endometriosis, and migraine.
• Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain.

Conclusions:

• The study identified a substantial number of genetic variants associated with generalized anxiety symptom severity.
• A dimensional approach to anxiety genetics, considering symptom severity, provides valuable insights.
• Anxiety shares genetic underpinnings with various other mental and physical health conditions, suggesting pleiotropy.