Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry.
Skelton M., Mitchell BL., Assary E., Li D., Morneau-Vaillancourt G., Murphy AE., Ter Kuile AR., Wang R., Adams MJ., Byrne EM., Corfield EC., Grimes PZ., Hannigan LJ., Hu J., Kõiv K., Kwong ASF., Papiol S., Pettersen JH., Pistis G., Castelao E., Strom NI., van der Most PJ., Anxiety Disorders Working Group of the Psychiatric Genomics Consortium ., GLAD+ authors ., Lifelines Cohort Study ., NIHR BioResource ., PROTECT-AD Consortium ., Andreassen OA., Erhardt-Lehmann A., Havdahl A., Skene N., Verhulst B., Weber H., Armour C., Ask H., Copeland WE., Dannlowski U., Deckert J., Domschke K., Hickie IB., Lehto K., Lonsdorf TB., Lueken U., Lupton MK., Medland SE., McIntosh AM., Oldehinkel AJ., Preisig M., Reif A., Snieder H., Walters JTR., Wray NR., Hartman CA., Martin NG., Hettema JM., Breen G., Coleman JRI., Eley TC.
Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. Here we performed a genome-wide association meta-analysis of generalized 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 newly associated with anxiety. SNP-based heritability was 5.9% (posterior s.d. = 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 (rg) were estimated with mental and physical health traits, including case-control anxiety, neuroticism and depression (rg = 0.71-0.85), 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 discovery power gained from analysing a quantitative trait rather than a case-control phenotype in anxiety genetics.