Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence

BACKGROUND: Chronic pain and internalising disorders such as anxiety and depression frequently co-occur during adolescence. Although prospective associations between internalising symptoms and later pain have been reported previously, the biological mechanisms underlying individual differences in this relationship remain poorly understood. Immune- and oxidative stress-related pathways, including the NRF2 gene, may contribute to such variability. This study investigated whether polymorphisms in the NRF2 gene (rs6721961 and rs35652124) are related to the association between anxiety and depression symptoms at age 14-15 and pain complaints two years later at age 16-17. METHODS: Data were drawn from the IMAGEN longitudinal study (N = 724). Anxiety and depression symptoms were assessed using the Development and Well-Being Assessment (DAWBA), and pain complaints were measured via the Children's Somatization Inventory (CSI). Genotyping was conducted for NRF2 SNPs rs6721961 and rs35652124. Regression analyses tested main effects, followed by genotype-stratified analyses. RESULTS: Consistent with previous literature, higher levels of anxiety and depression at age 14-15 predicted increased pain complaints at age 16-17. Carriers of the TG/TT genotype of rs6721961 had significantly lower anxiety scores and reported fewer pain complaints compared to those carrying the GG genotype of rs6721961. Notably, the association between anxiety and later pain was significant only among individuals with the GG genotype. CONCLUSION: While replicating established associations between adolescent early internalising symptoms and later pain, this study suggests that genetic variation in NRF2 is related to the anxiety-pain association. Specifically, rs6721961 is associated with differences in susceptibility to pain among adolescents with elevated anxiety symptoms.

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Journal
Communications Medicine
Published
2026-10-16
DOI
https://doi.org/10.1038/s43856-026-01960-5
Primary Topic
Psychosomatic Disorders and Their Treatments
Type
article
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article

Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence

Andreas Heinz, Sylvane Desrivières, Hugh P Garavan, Paul Wirsching et al.
Communications Medicine
Psychosomatic Disorders and Their Treatments
article

Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence

Andreas Heinz, Sylvane Desrivières, Hugh P Garavan, Paul Wirsching, Rüdiger Brühl, Tobias Banaschewski, Jean‐Luc Martinot, Arun L.W. Bokde, Nathalie E. Holz, Herta Flor, Antoine Grigis, Robert Whelan, Henrik Walter, Luise Poustka, Michael N. Smolka, Dimitri Papadopoulos Orfanos, Frauke Nees, Penny Anne Gowland, Eric Artiges A, Günter Schumann, Anh Cong Tuan Le, Nilakshi Vaidya, Dimitri Papadopoulos Orfanos, Marie-Laure Paillère Martinot
article en

Abstract

BACKGROUND: Chronic pain and internalising disorders such as anxiety and depression frequently co-occur during adolescence. Although prospective associations between internalising symptoms and later pain have been reported previously, the biological mechanisms underlying individual differences in this relationship remain poorly understood. Immune- and oxidative stress-related pathways, including the NRF2 gene, may contribute to such variability. This study investigated whether polymorphisms in the NRF2 gene (rs6721961 and rs35652124) are related to the association between anxiety and depression symptoms at age 14-15 and pain complaints two years later at age 16-17. METHODS: Data were drawn from the IMAGEN longitudinal study (N = 724). Anxiety and depression symptoms were assessed using the Development and Well-Being Assessment (DAWBA), and pain complaints were measured via the Children's Somatization Inventory (CSI). Genotyping was conducted for NRF2 SNPs rs6721961 and rs35652124. Regression analyses tested main effects, followed by genotype-stratified analyses. RESULTS: Consistent with previous literature, higher levels of anxiety and depression at age 14-15 predicted increased pain complaints at age 16-17. Carriers of the TG/TT genotype of rs6721961 had significantly lower anxiety scores and reported fewer pain complaints compared to those carrying the GG genotype of rs6721961. Notably, the association between anxiety and later pain was significant only among individuals with the GG genotype. CONCLUSION: While replicating established associations between adolescent early internalising symptoms and later pain, this study suggests that genetic variation in NRF2 is related to the anxiety-pain association. Specifically, rs6721961 is associated with differences in susceptibility to pain among adolescents with elevated anxiety symptoms.

Communications MedicineVol. 6(1)
University of Vermont (US), Technische Hochschule Mannheim (DE), École Normale Supérieure Paris-Saclay (FR), Physikalisch-Technische Bundesanstalt (DE), Centre National de la Recherche Scientifique (FR), University of Nottingham (GB), Inserm (FR), University of Mannheim (DE), King's College London (GB), Trinity College Dublin (IE), Heidelberg University (DE), Fudan University (CN), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), CEA Paris-Saclay - Etablissement de Saclay (FR), University Hospital Heidelberg (DE), Christian-Albrechts-Universität zu Kiel (DE), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Assistance Publique – Hôpitaux de Paris (FR), Central Institute of Mental Health (DE), University Hospital Schleswig-Holstein (DE), Pitié-Salpêtrière Hospital (FR), CEA Paris-Saclay (FR), Medizinische Fakultät Mannheim, Trajectoires développementales & psychiatrie, Centre Borelli (FR), Deutsches Zentrum für Psychische Gesundheit (DE), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), University of Minho (PT)
Fondation de l'Avenir pour la Recherche Médicale Appliquée, UK Research and Innovation, European Commission, Science Foundation Ireland, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Fondation de France, Fédération pour la Recherche sur le Cerveau, Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives, National Institutes of Health, HORIZON EUROPE Framework Programme, Medical Research Council
Good health and well-being
Openalex Percentile: Top 13%
Psychosomatic Disorders and Their Treatments
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