2026 ECNP Congress

PS01-1037

Aging-related long non-coding RNA expression in bipolar disorder: effects of familial liability and childhood trauma

Sultan Ekinci — B. Yeşiloğlu2,3, İ. Fettahoğlu, C. Pamukçu Ünlü, H.E. Arat Çelik5,, Ş. Hun Şenol, S. Balaç, E. Çörekli Kaymakçı, B. Kök Kendirlioğlu, M.A. Frye, A.Ö. Özerdem, M. Altıntaş, D. Ceylan · Erenköy Training and Research Hospital for Psychiatry and Neurological Diseases, Psychiatry Department, Istanbul, Türkiye

2026 ECNP Congress

Introduction

Bipolar disorder (BD) is associated with accelerated biological aging and premature mortality [1]. Long non-coding RNAs (lncRNAs) regulate cellular senescence, telomere maintenance, mitochondrial function, and inflammatory signaling pathways [2]. A previous systematic review of 112 articles identified seven aging-related lncRNAs to be highly relevant to BD pathophysiology [2]. We hypothesized that lncRNA dysregulation reflects familial liability to BD and is modulated by childhood trauma.

Methods

In this cross-sectional study, expression levels of seven aging-related lncRNAs were measured in peripheral blood mononuclear cells (PBMCs) from individuals with BD (n=68), their unaffected siblings (SIB; n=54), and healthy controls (HC; n=70), aged 18–50 years, using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Diagnoses were confirmed with SCID-5. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ), and lifestyle was assessed using the Health-Promoting Lifestyle Profile II (HPLP-II). Principal component analysis (PCA) was used to derive a composite lncRNA score. Group differences were analysed using analysis of covariance (ANCOVA) adjusted for age, sex, body mass index (BMI), and smoking status. Multivariable regression models tested the interaction between familial liability (defined as belonging to the BD or SIB groups vs HC) and childhood trauma.

Results

Nuclear-enriched abundant transcript 1 (NEAT1) and telomerase RNA component (TERC) were significantly elevated, while growth arrest-specific 5 (GAS5) was reduced in both BD and SIB compared with HC (all p<0.05). Taurine upregulated gene 1 (TUG1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) showed sibling-specific increases. PCA identified a dominant composite explaining 40.3% of variance, which was significantly higher in BD and SIB than HC (F=7.315, p=0.001), but similar in BD and SIB. ANCOVA revealed a significant main effect of familial liability (F(1,182)=8.18, p=0.005) and a significant interaction between familial liability and childhood trauma (defined as binary CTQ exposure) (F(1,182)=10.14, p=0.002). In multivariable regression, higher total CTQ scores (B=−0.004, p<0.001) and physical neglect (B=−0.020, p<0.001) were independently associated with lower composite scores, while familial liability remained a significant positive predictor (B=0.144, p<0.001). Clinical illness status (i.e., current BD diagnosis) and lifestyle factors were not independently associated with the lncRNA composite score.

Table 1.Comparison of lncRNA expression levels among study groups.

lncRNA BD vs HC SIB vs HC BD vs SIB Significance
NEAT1 ↑ ↑ ns p<0.001
TERC ↑ ↑ ns p<0.001
GAS5 ↓ ↓ ns p=0.014
TUG1 ns ↑ ns p=0.033
MALAT1 ns ↑ ↑ (SIB) p=0.020
Aging-related lncRNA composite ↑ ↑ ns p=0.001

ANCOVA model adjusted for age, sex, BMI, and smoking status ↑ elevated; ↓ reduced; ns not significant.

Conclusions

Aging-related lncRNA expression, particularly involving NEAT1, TERC, and GAS5, marks familial vulnerability to BD independent of diagnostic status, consistent with shared genetic and molecular mechanisms between BD and aging-related traits [3]. The familial liability × childhood trauma interaction supports a gene–environment mechanism in which early adversity, particularly physical neglect, attenuates lncRNA expression among genetically at-risk individuals, extending evidence linking childhood maltreatment to accelerated cellular aging [4]. These findings implicate convergent inherited predisposition and early-life stress in dysregulation of biological aging in BD, supporting a biologically heterogeneous vulnerability model and warranting longitudinal investigation.

References

  1. McIntyre, R.S., et al., 2020. Bipolar disorders. Lancet 396 (10265), 1841–1856.
  2. Ekinci, S., et al., 2026. Long non-coding RNAs and accelerated aging in bipolar disorder. Neurosci. Appl. 5, 106990.
  3. Bourdon, C., et al., 2023. Accelerated aging in bipolar disorders: an exploratory study of six epigenetic clocks. Psychiatry Res. 327, 115373.
  4. Aas, M., et al., 2020. Childhood maltreatment and accelerated telomere attrition in bipolar disorders. Psychol. Med. 50 (6), 963–971.