Abstract
Depression and anxiety are highly prevalent and comorbid psychiatric traits that cause considerable burden worldwide. Here we use factor analysis and genomic structural equation modelling to investigate the genetic factor structure underlying 28 items assessing depression, anxiety and neuroticism, a closely related personality trait. Symptoms of depression and anxiety loaded on two distinct, although highly genetically correlated factors, and neuroticism items were partitioned between them. We used this factor structure to conduct genome-wide association analyses on latent factors of depressive symptoms (89 independent variants, 61 genomic loci) and anxiety symptoms (102 variants, 73 loci) in the UK Biobank. Of these associated variants, 72% and 78%, respectively, replicated in an independent cohort of approximately 1.9 million individuals with self-reported diagnosis of depression and anxiety. We use these results to characterize shared and trait-specific genetic associations. Our findings provide insight into the genetic architecture of depression and anxiety and comorbidity between them.
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Data availability
All GWAS summary statistics generated from UK Biobank data are available from the authors upon request. Individual-level data for UK Biobank participants are available to eligible researchers through the UK Biobank (www.biobank.ac.uk). Access to 23andMe data is available upon request to 23andMe (further information is available from https://research.23andme.com/collaborate/).
Code availability
Code used to conduct analyses presented in this manuscript is available from the authors upon reasonable request.
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Acknowledgements
We thank the research participants of all cohorts for making this study possible. This work was conducted using the UK Biobank Resource (application number 25331). J.G.T. and A.I.C. are supported by a University of Queensland Research Training Scholarship. N.G.M. received funding from the Australian National Health and Medical Research Council (NHMRC) to conduct surveys in the QIMR Adult Twin Study. S.M. is supported by an NHMRC Fellowship.
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J.G.T. and E.M.D. conceived and directed the study. J.G.T. performed most of the statistical and bioinformatics analyses with the UK Biobank data, with support from A.I.C., A.D.G., Z.F.G., J.A., J.-S.O. and E.M.D. W.W., S.S. and the 23andMe Research Team conducted the replication analyses in the 23andMe cohort. A.I.C. conducted the polygenic risk prediction analyses, with support from J.G.T. N.G.M. collected and contributed data from the QIMR Adult Twin Study. Z.F.G., E.M.B., S.M., N.G.M., S.E.M., C.M.M. and E.M.D. provided methodological and psychiatric expertise. J.G.T. and E.M.D. wrote the manuscript, with all authors providing comments and suggestions.
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W.W., S.S. and members of the 23andMe Research Team are employees of 23andMe Inc. The other authors declare no competing interests.
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Thorp, J.G., Campos, A.I., Grotzinger, A.D. et al. Symptom-level modelling unravels the shared genetic architecture of anxiety and depression. Nat Hum Behav 5, 1432–1442 (2021). https://doi.org/10.1038/s41562-021-01094-9
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DOI: https://doi.org/10.1038/s41562-021-01094-9
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