Genetic overlap between functional impairment and depression and anxiety symptom severity: Evidence from the GLAD Study

Skelton, Megan, Mundy, Jessica, Kuile, Abigail, Adey, Brett, Armour, Cherie, Buckman, Joshua, Coleman, Jonathan, Davies, Molly, Hirsch, Colette, Hotopf, Matthew, Jones, Ian, Kalsi, Gursharan, Krebs, Georgina, Hyuck Lee, Sang, Lin, Yuhao, McIntosh, Andrew, Peel, Alicia, Rayner, Christopher, Rimes, Katharine, Smith, Daniel, Thompson, Katherine, Veale, David, Walters, James ORCID: https://orcid.org/0000-0002-6980-4053, Hubel, Christopher, Breen, Gerome and Eley, Thalia 2025. Genetic overlap between functional impairment and depression and anxiety symptom severity: Evidence from the GLAD Study. Psychological Medicine

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Abstract

Background Functional impairment in daily activities, such as work and socialising, is part of the diagnostic criteria for major depressive disorder (MDD) and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms and functional impairment. Methods In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analysed total scores from the Patient Health Questionnaire-9 (PHQ-9; depression symptoms), Generalised Anxiety Disorder-7 (GAD-7; anxiety symptoms), and Work and Social Adjustment Scale (WSAS; functional impairment). Genome-wide association analyses were performed with REGENIE. Heritability was estimated using GCTA-GREML and genetic correlations with bivariate-GREML. Results Phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50 - 0.69). All three scales were found to be under low but significant genetic influence (h2SNP = 0.11 - 0.19) with high genetic correlations between them (rg = 0.79 - 0.87). Conclusions Among individuals with lifetime depression or anxiety from the GLAD Study, the genetic variants that underlie symptom severity largely overlap with those influencing functional impairment. This suggests that self-reported functional impairment, while clinically relevant for diagnosis and treatment outcomes, does not reflect substantial additional genetic liability beyond that captured by symptom-based measures of depression or anxiety.

Item Type:	Article
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Cambridge University Press
ISSN:	0033-2917
Date of First Compliant Deposit:	26 June 2025
Date of Acceptance:	20 June 2025
Last Modified:	26 Jun 2025 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/179303

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