Exploratory factor analysis of shared and specific genetic associations in depression and anxiety

Previous genetic studies of anxiety and depression were mostly based on independent phenotypes. This study aims to investigate the shared and specific genetic structure between anxiety and depression.

To identify the underlying factors of Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and their combined scale (joint scale), we employed exploratory factor analysis (EFA) using the eigenvalue of parallel analysis. Subsequently, we conducted a genome-wide association study (GWAS) for these factors. In addition, we utilized LD Score Regression (LDSC) to determine the genetic correlations between the identified factors and four common mental disorders, three sleep phenotypes, and other traits that have been previously linked to anxiety and depression.

The EFA uncovered two factors for the GAD-7 scale, namely nervousness and disturbance, two factors for the PHQ-9 scale, namely negative affect and sleep/appetite disturbance, and four factors for the joint scale, specifically nervousness, anhedonia, sleep/appetite disturbance, and fidget. We identified two genome-wide significant genomic loci, with overlap across GAD-7 factor 1 and joint scale factor 1: rs148579586 (P_GAD-7 = 1.365 × 10^-09, P_{Joint scale} = 1.434 × 10^-09) and rs201074060 (P_GAD-7 = 3.672 × 10^-09, P_{Joint scale} = 3.824 × 10^-09). Genetic correlations in factors ranged from 0.722 to 1.000 (all p < 1.786 × 10^-03) with 27 of 28 correlations being significantly smaller than one. The genetic correlations with external phenotypes showed small variation across the eight factors.

Unidimensional structures can provide more precise scores, which can aid in identifying the shared and specific genetic associations between anxiety and depression. This is a crucial step in characterizing the genetic structure of these conditions and their co-occurrence.