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., Bacanu S-A., Cheesman R., Purves KL., Gedik H., Faucon AB., Singh K., Colodro-Conde L., Krebs K., Hoffmann P., Herms S., Gehlen J., Ripke S., Awasthi S., Palviainen T., Tasanko EM., Peterson RE., Adkins DE., Shabalin AA., Iveson MH., Campbell A., Thomas LF., Winsvold BS., Drange OK., Børte S., ter Kuile AR., Nguyen T-H., Meier SM., Levey DF., Czamara D., Choi KW., Couvy-Duchesne B., Van der Auwera S., Teumer A., Karlsson R., Garcia-Argibay M., Lee D., Bjerkeset O., Stordal E., Bäckmann J., Salum GA., Zai CC., Kennedy JL., Zai G., Tiwari AK., Heilmann-Heimbach S., Schmidt B., Kaprio J., Kennedy MM., Boden J., Middeldorp CM., Lopes FL., Akula N., McMahon FJ., Binder EB., Fehm L., Ströhle A., Tiemeier H., Stein DJ., Whiteman D., Olsen C., Fuller Z., Wang X., Lewis G., Timpson NJ., Davis LK., Gillespie NA., Milani L., Schumacher J., Woldbye DP., Forstner AJ., Nöthen MM., Hovatta I., Horwood J., Maes HH., Zwart J-A., Mors O., Børglum AD., Mortensen PB., Ask H., Reichborn-Kjennerud T., Najman JM., Stein MB., Gelernter J., Milaneschi Y., Penninx BW., Boomsma DI., Maron E., Rück C., Kircher TT., Melzig CA., Alpers GW., Arolt V., Smoller JW., Luik AI., Grabe HJ., Larsson H., Magnusson PK., Docherty AR., Coon H., Conrad R., Mattheisen M., Hotopf M., Jones IR., Smith DJ., Young AH., Cleare AJ., Davis KAS., Krebs G., Rimes KA., Veale D., Zahn R., Davies MR., Kalsi G., Bristow S., Curzons SCB., Rogers HC., Thompson KN., Adey BN., Marsh I., Monssen D., McAtarsney-Kovacs M., Curtis CJ., Arora J., Kakar S., Meldrum L., Smith I., Dowey LR., Gault V., Lyall DM., Price RK., Thomas KG., Ahmad Z., Davies HL., Hübel C., Lee SH., Lin YL., Maina JG., Mundy J., Palmos A., Peel AJ., Rayner C., Zvrskovec J., Aguirre-Gamboa R., Deelen P., Franke L., Kuivenhoven JA., Lopera Maya EA., Nolte IM., Sanna S., Swertz MA., Visscher PM., Vonk JM., Wijmenga C., Bradley J., Kingston N., Stark H., Kanz C., Moulton A., Ovington N., Lee J., Clapham-Riley D., Mills K., Wittchen U., Pittig A., Heinig I., Hoyer J., Fydrich T., Hamm A., Richter J., Arolt V., Kölkebeck K., Schneider S., Margraf J., Straube B., Rief W., Pauli P., Neudeck P., 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.
Abstract 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 ( R 2 = 1.2–2.9%). Significant genetic correlations ( r g ) were estimated with mental and physical health traits, including case–control anxiety, neuroticism and depression ( r g = 0.71–0.85), irritable bowel syndrome ( r g = 0.57), coronary artery disease, endometriosis and migraine ( r g = 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.