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

Skelton, M.; Mitchell, B. L.; Assary, E.; Li, D.; Morneau-Vaillancourt, G.; Murphy, A. E.; ter Kuile, A. R.; Wang, R.; Adams, M. J.; Byrne, E. M.; Corfield, E. C.; Grimes, P. Z.; Hannigan, L. J.; Hu, J.; Koiv, K.; Kwong, A. S.; Papiol, S.; Pettersen, J. H.; Pistis, G.; Castelao, E.; Strom, N. I.; van der Most, P. J.; Anxiety Disorders Working Group of the Psychiatric Genomics Consortium, ; GLAD+ authors, ; Lifelines Cohort Study, ; NIHR Bioresource, ; Protect-AD Consortium, ; Andreassen, O. A.; Erhardt-Lehmann, A.; Havdahl, A.; Skene, N.; Verhulst, B.; Weber, H.; Armour, C.; Ask, H.; Cope

2025-07-11 genetic and genomic medicine
10.1101/2025.07.10.25331321 medRxiv
Show abstract

We performed a genome-wide association meta-analysis of generalised anxiety symptom severity in 693,869 individuals of European ancestry from 14 cohorts. We identified 80 independent genome-wide significant variants within 74 loci, 39 of which were novel for anxiety. SNP-based heritability was 5.9% (SE = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African, and South Asian ancestry samples (r2=1.2%-2.9%). Significant genetic correlations were estimated with numerous mental and physical health traits, including case-control anxiety, neuroticism and depression (rg=0.71-0.86), irritable bowel syndrome (rg=0.57), coronary artery disease, endometriosis, and migraine (rg=0.20-0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain. These findings highlight the additional value of a quantitative approach in anxiety genetics.

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