Anxiety and Depression Traits Are Moderated by a Sex-Dependent Genetic Interaction Between 5-HTTLPR and BDNF.

Overview

1. Brain-Behavior Research Group, University of New England, Armidale, NSW 2350, Australia; (G.L.O.); (V.B.)

Abstract

Highlights: What are the main findings? The BDNF GA polymorphism has opposite effects depending on sex and 5-HTTLPR background. The interaction is selective for anxiety and anhedonic depression.

What are the implications of the main findings? Inverted vulnerability patterns between sexes underscore the potential importance of sex-specific approaches in psychiatric drug development and clinical care. Research should target specific subtypes rather than broad diagnoses to uncover meaningful associations.

Abstract: Background/Objectives: Depression and anxiety disorders exhibit significant clinical heterogeneity, which complicates diagnosis and treatment. This study investigated whether tripartite interactions between biological sex, the serotonin transporter gene promoter region (5-HTTLPR), and brain-derived neurotrophic factor (BDNF) G196A polymorphisms explain specific symptom-level variations. Methods: A community sample of 271 Australian adults was genotyped for common 5-HTTLPR (short/long) and BDNF (G/A) variants. Participants completed self-reported measures of anxiety (SAS), depression subtypes (SDS; clinical content scales), and psychological resilience (CDRISC). Morning salivary cortisol, BMI, and substance use were assessed as potential confounds. Statistical analyses utilised a three-way factorial ANCOVA to test for interactions on raw scores, controlling for age. Significant omnibus interactions were decomposed via planned stratified ANCOVAs within each 5-HTTLPR stratum. Results: The BDNF GA genotype exerted opposite effects on anxiety and anhedonia depending on sex and 5-HTTLPR background. In females, GA was associated with increased symptoms on an ss background, whereas in males, GA was associated with increased symptoms on an ll background. These effects were highly specific to anxiety and anhedonic depression, while depressed mood, cognitive, and somatic subtypes remained unaffected. Findings were independent of cortisol, BMI, smoking, alcohol use, and psychological resilience. Conclusions: The findings reveal a complex, sex-dependent genetic interaction that selectively influences anhedonia and anxiety. They should be interpreted in the context of modest subgroup sizes following genotype stratification and require replication in larger independent cohorts. Nonetheless, this study highlights the value of considering sex-stratified genetic backgrounds and symptom specificity to advance personalised precision medicine in psychiatry.

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Data Availability Statement

All data supporting the findings are within this paper and Appendix A.

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Version 2, 28 September 2026

• Funding: added University of New England

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 7 keywords, 97 references.

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This paper

Odierna, G. L., Sharpley, C. F., & Bitsika, V. (2026). Anxiety and Depression Traits Are Moderated by a Sex-Dependent Genetic Interaction Between 5-HTTLPR and BDNF. Brain sciences, 16(8), 883. https://doi.org/10.3390/brainsci16080883

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