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Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study

Nature Genetics volume 56, pages 2036–2045 (2024)Cite this article

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Abstract

We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.

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Fig. 1: Genetic correlations among anxiety phenotypes assessed in EUR participants.
Fig. 2: gSEM applied to anxiety phenotypes assessed in EUR individuals.
Fig. 3: Manhattan plots of genome-wide, transcriptome-wide and proteome-wide association statistics (bottom, center and top, respectively) related to ANX.
Fig. 4: Within-ancestry and cross-ancestry PRS associations of ANX.
Fig. 5: ANX pleiotropy with other psychiatric disorders.
Fig. 6: Phenome-wide genetic correlations of ANX.

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Data availability

The genome-wide association statistics generated by the current study are available in Zenodo (https://doi.org/10.5281/zenodo.13135834)105. GWAS-data-related cohorts included in this study were derived from the following sources: AoU, https://workbench.researchallofus.org/; FinnGen, https://www.finngen.fi/en/access_results; iPSYCH, https://ipsych.dk/en/research/downloads; MVP, https://www.ncbi.nlm.nih.gov/projects/gap/; PGC, https://pgc.unc.edu/for-researchers/download-results/; UKB, https://pan.ukbb.broadinstitute.org/.

Code availability

The study used the following computational packages: gSEM, https://github.com/GenomicSEM/GenomicSEM; METAL, https://github.com/statgen/METAL; GCTA-COJO, https://yanglab.westlake.edu.cn/software/gcta/#COJO; PAINTOR, https://github.com/gkichaev/PAINTOR_V3.0; LDSC, https://github.com/bulik/ldsc; PRS-CS, https://github.com/getian107/PRScs; PLINK, https://www.cog-genomics.org/plink/; MetaXcan, https://github.com/hakyimlab/MetaXcan; FUSION, https://github.com/gusevlab/fusion_twas; HyPrColoc, https://github.com/cnfoley/hyprcoloc; LAVA, https://github.com/josefin-werme/LAVA; MixeR, https://github.com/precimed/mixer; LCV, https://github.com/lukejoconnor/LCV; CAUSE, https://github.com/jean997/cause; MRlap, https://github.com/n-mounier/MRlap.

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Acknowledgements

This study was supported by grants from the National Institutes of Health (RF1 MH132337 to R.P., R33 DA047527 to R.P. and K99 AG078503 to G.A.P.), One Mind (to R.P.), the Alzheimer’s Association (Research Fellowship AARF-22-967171 to G.A.P.), the American Foundation for Suicide Prevention (PDF-1-022-21 to B.C.M.), Horizon 2020 (Marie Sklodowska-Curie Individual Fellowship 101028810 to D.K.), the University of Bergen (International Training Grant to S.L.) and the Yale Franke Program in Science and Humanities (to B.C.M.). We also acknowledge the contribution of the participants and the investigators involved in the UKB, the FinnGen Project, the MVP, the AoU Research Program, the iPSYCH study and the PGC. The AoU Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Eleni Friligkou, Solveig Løkhammer, Brenda Cabrera-Mendoza, Jie Shen, Jun He, Giovanni Deiana, Mihaela Diana Zanoaga, Zeynep Asgel, Abigail Pilcher, Luciana Di Lascio, Ana Makharashvili, Dora Koller, Daniel S. Tylee, Gita A. Pathak & Renato Polimanti

  2. Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT, USA

    Eleni Friligkou, Brenda Cabrera-Mendoza, Jun He, Ana Makharashvili, Gita A. Pathak & Renato Polimanti

  3. Department of Clinical Science, University of Bergen, Bergen, Norway

    Solveig Løkhammer

  4. Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    Solveig Løkhammer

  5. Department of Cardiology, Children’s Hospital of Soochow University, Suzhou, China

    Jie Shen

  6. Center for Neuroscience, Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy

    Giovanni Deiana

  7. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland

    Mihaela Diana Zanoaga

  8. Department of Child and Adolescent Psychiatry, NYU Langone Health, New York Metropolitan Area, New York, NY, USA

    Zeynep Asgel

  9. IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy; Humanitas University, Pieve Emanuele, Milan, Italy

    Luciana Di Lascio

  10. Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain

    Dora Koller

  11. Wu Tsai Institute, Yale University, New Haven, CT, USA

    Renato Polimanti

  12. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA

    Renato Polimanti

  13. Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT, USA

    Renato Polimanti

Authors
  1. Eleni Friligkou
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  2. Solveig Løkhammer
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  3. Brenda Cabrera-Mendoza
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  4. Jie Shen
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  5. Jun He
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  6. Giovanni Deiana
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  7. Mihaela Diana Zanoaga
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  8. Zeynep Asgel
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  9. Abigail Pilcher
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  10. Luciana Di Lascio
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  11. Ana Makharashvili
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  12. Dora Koller
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  13. Daniel S. Tylee
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  14. Gita A. Pathak
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  15. Renato Polimanti
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Contributions

E.F. and R.P. designed the study. E.F., S.L., B.C.M., J.S., J.H., G.D., M.D.Z., Z.A., A.P., L.D.L., D.K., D.S.T., G.A.P. and R.P. conducted computational and statistical analyses. E.F., S.L., B.C.M., J.S., J.H., G.D., M.D.Z., Z.A., A.P., L.D.L., A.M., D.K., D.S.T., G.A.P. and R.P. interpreted the results. E.F. and R.P. wrote the initial draft of the manuscript. E.F., S.L., B.C.M., J.S., J.H., G.D., M.D.Z., Z.A., A.P., L.D.L., A.M., D.K., D.S.T., G.A.P. and R.P. provided comments and revised the manuscript. R.P. obtained the primary funding for the study and supervised the analyses.

Corresponding author

Correspondence to Renato Polimanti.

Ethics declarations

Competing interests

R.P. is paid for editorial work on the journal Complex Psychiatry and reports a research grant from Alkermes outside the scope of the present study. D.K. is the founder of EndoCare Therapeutics. The remaining authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–3.

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Supplementary Tables

Supplementary Tables 1–23.

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Friligkou, E., Løkhammer, S., Cabrera-Mendoza, B. et al. Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study. Nat Genet 56, 2036–2045 (2024). https://doi.org/10.1038/s41588-024-01908-2

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