Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry, 2026, Skelton et al.

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Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry

Spoiler: Authors

Skelton, Megan; Mitchell, Brittany L; Assary, Elham; Li, Danyang; Morneau-Vaillancourt, Genevieve; Murphy, Alan E; ter Kuile, Abigail R; Wang, Rujia; Adams, Mark J; Byrne, Enda M; Corfield, Elizabeth C; Grimes, Poppy Z; Hannigan, Laurie J; Hu, Jihua; Kõiv, Kadri; Kwong, Alex S F; Papiol, Sergi; Pettersen, Johanne H; Pistis, Giorgio; Castelao, Enrique; Strom, Nora I; van der Most, Peter J; Andreassen, Ole A; Erhardt-Lehmann, Angelika; Havdahl, Alexandra; Skene, Nathan; Verhulst, Brad; Weber, Heike; Armour, Chérie; Ask, Helga; Copeland, William E; Dannlowski, Udo; Deckert, Jürgen; Domschke, Katharina; Hickie, Ian B; Lehto, Kelli; Lonsdorf, Tina B; Lueken, Ulrike; Lupton, Michelle K; Medland, Sarah E; McIntosh, Andrew M; Oldehinkel, Albertine J; Preisig, Martin; Reif, Andreas; Snieder, Harold; Walters, James T R; Wray, Naomi R; Hartman, Catharina A; Martin, Nicholas G; Hettema, John M; Breen, Gerome; Coleman, Jonathan R I; Eley, Thalia C

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.

Web | DOI | PDF | Nature Human Behaviour | Open Access

 

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The strongest intragenic association was estimated for rs1476548 within PCLO, which was also implicated through positional mapping, eQTL mapping and gene-based association testing. PCLO encodes a protein involved in regulating presynaptic structure and neurotransmitter release. This gene has long been of interest in major depressive disorder, with recent evidence also linking it to anxiety disorders.

Another gene of interest from our analysis was SORCS3, which was supported by multiple lines of evidence in the recent PGC-ANX case–control anxiety GWAS. SORCS3 plays a role in postsynaptic functioning and glutamate receptor regulation, particularly in the hippocampus. It has been linked to memory and learning processes, specifically synaptic depression and fear extinction, and mental health and neurodevelopmental conditions, including major depressive disorder, Tourette syndrome, attention deficit hyperactivity disorder and autism.

A network medicine approach to investigating ME/CFS pathogenesis in severely ill patients: a pilot study (2025) —

We examined the nine genes with recurrent variants in the SIPS patients, specifically ACADL, BRCA1, CFTR, COX10, HABP2, MFRP, PCLO, PRKN, and ZFPM2.

SORCS3 came up in Genome-wide association study of multisite chronic pain in UK Biobank (2019)