Neuroticism as a predictor of frailty in old age: a genetically informative approach

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ObjectiveNeuroticism is associated with poor health outcomes, but its contribution to the accumulation of health deficits in old age, i.e. the frailty index, is largely unknown. We aimed to explore associations between neuroticism and frailty cross-sectionally and longitudinally, and to investigate the contribution of shared genetic influences.MethodData were derived from the UK Biobank (UKB, n=274,951), the Australian Over 50’s Study (AO50, n=2,849) and the Swedish Twin Registry (SALT n=18,960, SATSA n=1,365). Associations between neuroticism and the frailty index were investigated using regression analysis cross-sectionally in UKB, AO50 and SATSA, and longitudinally in SALT (25-29y follow-up) and SATSA (6 and 23y follow-up). The co-twin control method was applied to explore the contribution of underlying shared familial factors (SALT, SATSA, AO50). Genome-wide polygenic risk scores for neuroticism were used in all samples to further assess whether common genetic variants associated with neuroticism predict frailty.ResultsHigh neuroticism was consistently associated with greater frailty cross-sectionally (adjusted β [95% confidence intervals] in UKB=0.32[0.32-0.33]; AO50=0.35[0.31-0.39]; SATSA=0.33[0.27-0.39]) and longitudinally up to 29 years (SALT=0.24[0.22-0.25]; SATSA 6y=0.31[0.24-0.38]; SATSA 23y=0.16[0.07-0.25]). When adjusting for underlying shared genetic and environmental factors the neuroticism-frailty association remained significant, although decreased. Polygenic risk scores for neuroticism significantly predicted frailty in the two larger samples (meta-analyzed total β=0.059[0.055-0.062]).ConclusionNeuroticism in mid-life predicts frailty in late-life. Neuroticism may have a causal influence on frailty, whereas both environmental and genetic influences, including neuroticism-associated common genetic variants, contribute to this relationship.

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