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Frailty and depression share substantial genetics, with one condition predisposing to the other and comorbidity supported by large-scale genome-wide association studies (GWAS).

The bi-directional, causal association that was identified remained in place after accounting for age as well as physical activity, researchers from China report in the journal Science Advances.

“On the basis of our findings, it is reasonable to consider promoting routine frailty screening in depression patients,” reported Ming-Gang Deng, from Wuhan Mental Health Center, and colleagues.

Frailty is a state of vulnerability across multiple physiologic systems that includes a reduced ability to cope with stressors and an increased risk of falls, disability, long-term care, and death.

Depression meanwhile is the most common mental health illness and can include long-lasting low mood, anxious feelings, cognitive impairment, and physical symptoms.

Although numerous epidemiological studies have found associations between the two, a causal relationship remains unclear.

To investigate further, Deng and co-workers used GWAS data as these large datasets have previously identified thousands of genetic variations related to various complex diseases.

GWASs have promoted the widespread use of Mendelian Randomization, a method in which genetics is used to study behaviors or environments that cause disease.

The team therefore applied this system of analysis to frailty data collected from the U.K. Biobank and TwinGen meta-analysis and depression data obtained from  the Psychiatric Genomics Consortium and FinnGen.

Linkage disequilibrium score regression revealed that frailty had a moderate genetic correlation with depression in the latter two datasets.

In univariate analysis, genetically predicted higher frailty index was related to a significantly elevated odds ratio of depression, at 1.86 in the Psychiatric Genomics Consortium and 1.75 in FinnGen.

Using genetic liability for the above two datasets as exposures also revealed a causal effect for depression on frailty index.

After adjusting for BMI, which was the major confounding factor in the association between frailty and depression, higher frailty index remained associated with elevated risks for depression in the Psychiatric Genomics Consortium and FinnGen datasets, with corresponding odds ratios of 1.64 and 1.46.

Depressed people were also significantly more likely to have a higher frailty index in  multivariate analysis.

Sensitivity analyses supported this bidirectional causal relationship, which remained stable after adjusting for physical activity.

The researchers note that the original frailty GWAS summary statistics reported 14 genome-wide significant risk loci and two loci that had significant associations with depression or depressive symptoms.

They suggest that adverse outcomes from frailty such as falls, higher medical costs, and less social interaction could subsequently lead to anxiety, and ultimately result in depression.

“On the other hand, depression could lead to poor nutritional status, sleep disturbance, and emotional disorders, which may seriously affect physical health and cause frailty.”

Depression is associated with cognitive impairment and this may also lead to the appearance of frailty, the researchers pointed out.

In addition, there is growing evidence that the bidirectional association could be partially explained by shared risk factors and pathophysiological pathways, such as chronic inflammation, oxidative stress, mitochondrial dysfunction, and hypothalamic adrenal axis dysregulation.

“It is worth noting that both frailty and depression are associated with a series of deleterious results such as decreased quality of life and increased use of health care services,” the authors added.

“Coexisting frailty and depression even led to accelerated cognitive impairment, disability, and death.

“Therefore, providing timely psychological comfort and psychological guidance to frail patients or screening depressed patients for frailty are both necessary.”

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