Genome-wide analyses of quantitative generalised anxiety symptom severity

Megan Skelton; Brittany L. Mitchell; Elham Assary; Danyang Li; Geneviève Morneau‐Vaillancourt; Alan E Murphy; Abigail ter Kuile; Rujia Wang; Mark J. Adams; Enda M. Byrne; Elizabeth C. Corfield; Poppy Zenzi Grimes; Laurie J. Hannigan; Jihua Hu; Kadri Kõiv; Alex S. F. Kwong; Sergi Papiol; Johanne Hagen Pettersen; Giorgio Pistis; Enrique Castelao; Nora I. Strom; Peter J. van der Most; GLAD+ authors; Lifelines Cohort Study; NIHR Bioresource; Ole A. Andreassen; Angelika Erhardt; Alexandra Havdahl; Nathan Skene; Brad Verhulst

doi:10.1101/2025.07.10.25331321

Genetic & Genomic MedicinemedRxivJul 10, 2025

Preprint

Genome-wide analyses of quantitative generalised anxiety symptom severity

Megan Skelton iD, Brittany L. Mitchell iD, Elham Assary iD, Danyang Li iD, Geneviève Morneau‐Vaillancourt iD, Alan E Murphy iD, Abigail ter Kuile iD, Rujia Wang iD, Mark J. Adams iD, Enda M. Byrne iD, Elizabeth C. Corfield iD, Poppy Zenzi Grimes iD, Laurie J. Hannigan iD, Jihua Hu iD, Kadri Kõiv iD, Alex S. F. Kwong iD, Sergi Papiol iD, Johanne Hagen Pettersen iD, Giorgio Pistis iD, Enrique Castelao iD, Nora I. Strom iD, Peter J. van der Most iD, GLAD+ authors, Lifelines Cohort Study, NIHR Bioresource, , Thalia Catherine Eley iD

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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