Frailty and psychiatric disorders: A bidirectional Mendelian randomization study

J Affect Disord. 2024 Jul 1:356:346-355. doi: 10.1016/j.jad.2024.04.024. Epub 2024 Apr 16.


Background: The association between frailty and psychiatric disorders has been reported in observational studies. However, it is unclear whether frailty facilitates the appearance of psychiatric disorders or vice versa. Therefore, we conducted a bidirectional Mendelian randomization (MR) study to evaluate the causality.

Methods: Independent genetic variants associated with frailty index (FI) and psychiatric disorders were obtained from large genome-wide association studies (GWAS). The inverse variance weighted method was utilized as the primary method to estimate causal effects, followed by various sensitivity analyses. Multivariable analyses were performed to further adjust for potential confounders.

Results: The present MR study revealed that genetically predicted FI was significantly and positively associated with the risk of major depressive disorder (MDD) (odds ratio [OR] 1.79, 95 % confidence interval [CI] 1.48-2.15, P = 1.06 × 10-9), anxiety disorder (OR 1.61, 95 % CI 1.19-2.18, P = 0.002) and neuroticism (OR 1.38, 95 % CI 1.18-1.61, P = 3.73 × 10-5). In the reverse MR test, genetic liability to MDD (beta 0.232, 95 % CI 0.189-0.274, P = 1.00 × 10-26) and neuroticism (beta 0.128, 95 % CI 0.081-0.175, P = 8.61 × 10-8) were significantly associated with higher FI. Multivariable analyses results supported the causal association between FI and MDD and neuroticism.

Limitations: Restriction to European populations, and sample selection bias.

Conclusions: Our study suggested a bidirectional causal association between frailty and MDD neuroticism, and a positive correlation of genetically predicted frailty on the risk of anxiety disorder. Developing a deeper understanding of these associations is essential to effectively manage frailty and optimize mental health in older adults.

Keywords: Causal relationship; Frailty index; Mendelian randomization; Older people; Psychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anxiety Disorders* / epidemiology
  • Anxiety Disorders* / genetics
  • Depressive Disorder, Major* / epidemiology
  • Depressive Disorder, Major* / genetics
  • Female
  • Frailty* / epidemiology
  • Frailty* / genetics
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Mendelian Randomization Analysis*
  • Mental Disorders / epidemiology
  • Mental Disorders / genetics
  • Neuroticism*
  • Polymorphism, Single Nucleotide