Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence.
Le Anh Cong Tuan, Banaschewski Tobias, Bokde Arun L W, Brühl Rüdiger, Desrivières Sylvane, Garavan Hugh, Gowland Penny, Grigis Antoine, Heinz Andreas, Martinot Jean-Luc, Martinot Marie-Laure Paillère, Artiges Eric, Orfanos Dimitri Papadopoulos, Poustka Luise, Smolka Michael N, Holz Nathalie, Vaidya Nilakshi, Walter Henrik, Whelan Robert, Wirsching Paul, Schumann Gunter, Flor Herta, Nees Frauke
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.
Key Findings
- Higher anxiety and depression symptoms at age 14-15 predict increased pain complaints at age 16-17.
- Carriers of the TG/TT genotype of NRF2 SNP rs6721961 have lower anxiety scores and fewer pain complaints compared to GG genotype carriers.
- The association between anxiety and later pain is significant only among individuals with the GG genotype of rs6721961.
Clinical Significance
Genetic variation in the NRF2 gene influences the relationship between anxiety and pain in adolescents, suggesting potential for personalized interventions targeting oxidative stress pathways to mitigate pain outcomes in youth with internalizing symptoms.
Citation
Le Anh Cong Tuan, Banaschewski Tobias, Bokde Arun L Wet al.. Immune-related gene expression links anxiety, depression, and pain outcomes in adolescence. Communications medicine. 2026-Oct-16.