Genetic and environmental risk factors for major depression in UK women and their association with telomere length longitudinally

BACKGROUND: Major depressive disorder (MDD) is more prevalent in women and associated with shorter telomere length, a marker of biological ageing, and an increased risk of age-related disease. However, the precise influence of depression-related genetic and environmental risk factors on telomere dynamics remains a topic of debate. METHODS: We examined leukocyte relative telomere length (RTL) and longitudinal telomere attrition in 958 women (median age: 58 years) from the TwinsUK cohort. RTL was measured using quantitative PCR from up to four timepoints. Associations with self-reported depression, antidepressant use, lifestyle and socioeconomic factors, and polygenic risk scores (PGS) for MDD and comorbid age-related diseases were assessed using linear mixed models. RESULTS: Over a median 6-year follow-up, telomere length declined annually by 1.3 % of baseline RTL. Depression showed a borderline association with shorter RTL (p = 0.06), while a nominal association was observed between antidepressant use and shorter RTL (p = 0.02), replicating previous findings. No significant associations were observed for PGS related to MDD. PGS for coronary artery disease was associated with shorter RTL (p = 0.02), while other trait PGS showed inconsistent associations with RTL or attrition. Higher waist-to-hip ratio was associated with faster telomere attrition longitudinally (p = 0.01). CONCLUSIONS: Our findings suggest depression and its genetic liability are not directly associated with telomere length or attrition in older women. In contrast, waist-to-hip ratio, a modifiable factor, was linked to accelerated telomere shortening, pointing to central adiposity as a potential intervention target with relevance for both mental and physical health.