Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence
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.
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BibTeX
@article{le2026immunerelated,
title = {{Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence}},
author = {Anh Cong Tuan Le and Tobias Banaschewski and Arun L. W. Bokde and Rüdiger Brühl and Sylvane Desrivières and Hugh Garavan and Penny Gowland and Antoine Grigis and Andreas Heinz and Jean-Luc Martinot and Marie-Laure Paillère Martinot and Eric Artiges and Dimitri Papadopoulos Orfanos and Luise Poustka and Michael N. Smolka and Nathalie Holz and Nilakshi Vaidya and Henrik Walter and Robert Whelan and Paul Wirsching and Gunter Schumann and Herta Flor and Frauke Nees and IMAGEN Consortium and Dimitri Papadopoulos Orfanos},
journal = {Communications Medicine},
year = {2026},
month = oct,
doi = {10.1038/s43856-026-01960-5},
url = {https://www.nature.com/articles/s43856-026-01960-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence
AU - Anh Cong Tuan Le
AU - Tobias Banaschewski
AU - Arun L. W. Bokde
AU - Rüdiger Brühl
AU - Sylvane Desrivières
AU - Hugh Garavan
AU - Penny Gowland
AU - Antoine Grigis
AU - Andreas Heinz
AU - Jean-Luc Martinot
AU - Marie-Laure Paillère Martinot
AU - Eric Artiges
AU - Dimitri Papadopoulos Orfanos
AU - Luise Poustka
AU - Michael N. Smolka
AU - Nathalie Holz
AU - Nilakshi Vaidya
AU - Henrik Walter
AU - Robert Whelan
AU - Paul Wirsching
AU - Gunter Schumann
AU - Herta Flor
AU - Frauke Nees
AU - IMAGEN Consortium
AU - Dimitri Papadopoulos Orfanos
PY - 2026
DA - 2026/10/16
JO - Communications Medicine
DO - 10.1038/s43856-026-01960-5
UR - https://www.nature.com/articles/s43856-026-01960-5
AB - 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.
SN - 2730-664X
ER -