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Using phenotype risk scores to enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder

Molecular Psychiatry volume 27, pages 2206–2215 (2022)Cite this article

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Abstract

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire (“MHQ responders”). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB participants lacking MHQ data (“MHQ non-responders”; NTraining = 50%; NTest = 50%), maximizing the informative sample for these traits. MHQ responders were more likely to be female, from higher socioeconomic positions, and less anxious than non-responders. Genetic correlation of GAD and PTSD between MHQ responders and non-responders ranged from 0.636 to 1.08; both were predicted by polygenic scores generated from independent cohorts. In meta-analyses of GAD (N = 489,579) and PTSD (N = 497,803), we discovered many novel genomic risk loci (13 for GAD and 40 for PTSD). Transcriptomic analyses converged on altered regulation of prenatal dorsolateral prefrontal cortex in these disorders. Our results provide one roadmap by which sample size and statistical power may be improved for gene discovery of incompletely ascertained traits in the UKB and other biobanks with limited mental health assessment.

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Fig. 1: Study design for understanding the genetic architectures of internalizing co-phenomes.
Fig. 2: Verifying the concordant genetic architectures of true and predicted internalizing outcomes.
Fig. 3: SNP annotation of GAD and PTSD GWAS.
Fig. 4: Out-sample polygenic prediction of relevant phenotypes.
Fig. 5: Prenatal transcriptomic signatures of GAD and PTSD outcomes.

Data availability

All data used to generate figures for this study are provided as Supplementary Material. Elastic net weights are provided as Supplementary Material. GWAS summary data are accessible at 10.5281/zenodo.4767570. This research has been conducted using the UK Biobank Resource (application reference no. 58146) and is available to bona fide researchers through approved access. Out-sample polygenic risk scoring utilized the Yale-Penn cohort (dbGaP Study Accession: phs000425.v1.p1) and the Philadelphia Neurodevelopmental Cohort (dbGaP Study Accession: phs000607.v3.p2). The dbGAP data used herein are available for approved access download from dbGAP data request portal.

Code availability

Previously developed pipelines were used to produce the results for this study. No custom code was developed to generate the data used to draw any of our conclusions.

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Acknowledgements

This research has been conducted using the UK Biobank Resource (application reference no. 58146). The authors thank the research participants and employees of the UK Biobank for making this work possible. This study was supported by National Institutes of Health (R21 DC018098, R21 DA047527, R33 DA047527, and F32 MH122058) and a Faculty Scholar Award from the Seaver Foundation: “Analytical Genomics of Vulnerable Populations.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

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

    Frank R. Wendt, Gita A. Pathak, Joseph D. Deak, Flavio De Angelis, Dora Koller, Brenda Cabrera-Mendoza, Daniel F. Levey, Joel Gelernter & Renato Polimanti

  2. VA CT Healthcare System, West Haven, CT, USA

    Frank R. Wendt, Gita A. Pathak, Joseph D. Deak, Flavio De Angelis, Dora Koller, Brenda Cabrera-Mendoza, Daniel F. Levey, Joel Gelernter & Renato Polimanti

  3. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Dannielle S. Lebovitch & Laura M. Huckins

  4. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Dannielle S. Lebovitch & Laura M. Huckins

  5. Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Dannielle S. Lebovitch & Laura M. Huckins

  6. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Dannielle S. Lebovitch & Laura M. Huckins

  7. VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA

    Murray B. Stein

  8. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  9. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  10. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Henry R. Kranzler

  11. Mental Illness Research, Education, and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, 19104, USA

    Henry R. Kranzler

  12. Broad Institute of MIT and Harvard, Stanley Center for Psychiatry Research, Cambridge, MA, USA

    Karestan C. Koenen

  13. Massachusettes General Hospital, Psychiatry and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA

    Karestan C. Koenen

  14. Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA

    Karestan C. Koenen

  15. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

  16. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

  17. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Laura M. Huckins

  18. Mental Illness Research, Education and Clinical Center, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, 10468, USA

    Laura M. Huckins

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  1. Frank R. Wendt
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Contributions

FRW and RP conceived the study design; FRW performed phenotype prediction, demographic comparisons, multi-trait conditioning, genome-wide association study meta-analyses, causal inference analysis, functional annotation, and PRS in the PNC; GAP performed fine mapping; JDD assisted with multi-trait conditioning; FDA performed drug repurposing analyses; DK performed genetic correlation; BCM performed GWAS statistics-level PRS; FRW, GAP, JDD, DSL, DFL, MBS, HRK, KCK, JG, LMH, and RP contributed to data interpretation; FRW, GAP and RP contributed to data visualization and presentation; FRW drafted the original manuscript. All authors critically evaluated and revised the manuscript.

Corresponding authors

Correspondence to Frank R. Wendt or Renato Polimanti.

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Competing interests

HRK is a member of an advisory board for Dicerna Pharmaceuticals, a consultant to Sophrosyne Pharmaceuticals, a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which for the past 3 years was supported by AbbVie, Alkermes, Amygdala Neurosciences, Arbor, DIicerna, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer, and is paid for his editorial work on the journal Alcoholism: Clinical and Experimental Research. HRK and JG are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. MBS is paid for his editorial work on the journals Biological Psychiatry and Depression and Anxiety, and the health professional reference Up-To-Date; he has also in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech, and has stock options in Oxeia Biopharmaceuticals and Epivario. RP and JG are paid for their editorial work on the journal Complex Psychiatry. The other authors have no competing interests to report.

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Wendt, F.R., Pathak, G.A., Deak, J.D. et al. Using phenotype risk scores to enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder. Mol Psychiatry 27, 2206–2215 (2022). https://doi.org/10.1038/s41380-022-01469-y

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