A genome‐wide association study of the frailty index highlights brain pathways in ageing

Atkins, Janice L.; Jylhävä, Juulia; Pedersen, Nancy L.; Magnusson, Patrik K. E.; Lu, Yi; Wang, Yunzhang; Hägg, Sara; Melzer, David; Williams, Dylan M; Pilling, Luke C.

doi:10.1111/acel.13459

Cited by 160 publications

(158 citation statements)

References 62 publications

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“…Furthermore, it also did not support the genetic causal links between FI and AD‐by‐proxy, a condition that shares strong genetic correlation with AD. By genetic risk score analysis, Atkins et al reported that AD may not influence frailty risk [15]. Therefore, the causal association between frailty and AD needs further investigation and more genetic variants, common pathways and shared risk factors related to the conditions need to be revealed.…”

Section: Discussionmentioning

confidence: 99%

“…By genetic risk score analysis, Atkins et al reported that AD may not influence frailty risk [15]. Therefore, the causal association between frailty and AD needs further investigation and more genetic variants, common pathways and shared risk factors related to the conditions need to be revealed.…”

Section: Discussionmentioning

confidence: 99%

“…between FI and stroke or AD. In addition, the potential confounding factors, like BMI, CRP, IBD and WHR, which were reported by Atkins et al [15], were also investigated by multivariable analysis.…”

Section: Discussionmentioning

confidence: 99%

“…The large sample size of GWAS and strong genetic variants in MR analysis have provided strong power to identify the causal association between FI and stroke or AD. In addition, the potential confounding factors, like BMI, CRP, IBD and WHR, which were reported by Atkins et al [15], were also investigated by multivariable analysis.…”

Section: Discussionmentioning

confidence: 99%

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Genetically predicted frailty index and risk of stroke and Alzheimer's disease

Liu

Fang

Gao

et al. 2022

Euro J of Neurology

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Background and purpose Previous studies have reported the association between frailty and stroke or Alzheimer's disease (AD). However, the causality remains unclear. The aim of the present study was to evaluate whether genetically predicted frailty is associated with the risk of stroke or AD by a Mendelian randomization (MR) study. Methods Genetic variants associated with the frailty index (FI) were obtained from a large genome‐wide association study (GWAS). Summary‐level data for stroke and AD were adopted from the corresponding large GWAS of individuals of European ancestry. The inverse variance weighted method was used for estimating causal effects. Multivariable analysis was performed for further adjustment. Results The present MR study indicated a suggestive association between genetically predicted FI and a higher risk of any stroke (odds ratio 1.360, 95% confidence interval 1.006–1.838, p = 0.046). Regarding the subtypes of stroke, genetically predicted FI was associated with a higher risk of large artery atherosclerosis stroke (LAS) (odds ratio 2.487, 95% confidence interval 1.282–4.826, p = 0.007). No causal links were identified between genetically predicted FI and any ischaemic stroke, intracranial haemorrhage, cardioembolic stroke, small artery stroke, AD or AD‐by‐proxy. Multivariable MR analysis indicated that the association of genetically predicted FI with LAS was attenuated after adjustment for inflammatory bowel disease (p = 0.114). Conclusions The MR study suggested that genetically predicted FI may be associated with an increased risk of any stroke. Subgroup analysis indicated a suggestive association between genetically predicted FI and the risk of LAS. The underlying mechanisms need further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetically predicted frailty index and risk of stroke and Alzheimer's disease

Liu

Fang

Gao

et al. 2022

Euro J of Neurology

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“…Our study provides limited insight into the causal relationships between mental disorders and frailty in relation to mortality. However, it is likely that mental illness and frailty are mutually reinforcing, and may share common risk factors 50 . Finally, we cannot exclude the possibility of residual confounding, and other variables (e.g., genetics, healthcare access or drug prescriptions) not considered here may also affect the observed associations.…”

Section: Discussionmentioning

confidence: 99%

Frailty in individuals with depression, bipolar disorder and anxiety disorders: longitudinal analyses of all-cause mortality

Mutz

Choudhury

Zhao

et al. 2022

Preprint

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Background: Frailty is a medical syndrome that is strongly associated with mortality risk, and an emerging global health burden. Mental disorders are associated with reduced life expectancy and elevated levels of frailty. In this study, we examined the mortality risk associated with frailty in individuals with a lifetime history of mental disorders compared to non-psychiatric controls. Methods: The UK Biobank study recruited >500,000 adults, aged 37-73, between 2006-2010. We derived the two most common albeit distinctive measures of frailty, the frailty phenotype and the frailty index. Individuals with lifetime depression, bipolar disorder or anxiety disorders were identified from multiple data sources. The primary outcome was all-cause mortality. We have also examined differences in frailty, separately by sex and age. Outcomes: Analyses included up to 297,380 middle-aged and older adults with a median follow-up of 12.19 (IQR=1.31) years, yielding 3,516,706 person-years of follow-up. We observed higher levels of frailty in individuals with mental disorders for both frailty measures. For key comparisons, individuals with a mental disorder had greater all-cause mortality hazards than their controls. The highest hazard ratio (3.65, 95% CI 2.40-5.54) was observed among individuals with bipolar disorder and frailty, relative to the non-frail controls. Interpretation: Our findings highlight elevated levels of frailty across three common mental disorders. The increased mortality risk associated with frailty and mental disorders represents a potentially modifiable target for prevention and treatment to improve life expectancy. Funding: Biotechnology and Biological Sciences Research Council.

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Modifiable Lifestyle, Sedentary Behaviors and the Risk of Frailty: A Univariate and Multivariate Mendelian Randomization Study

Yu,

Guo,

Long

et al. 2024

Advanced Biology

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This research conducted a two‐sample univariate and multivariate Mendelian Randomization (MR) analysis to explore the causal link between different types of leisure sedentary behavior (LSB) and frailty. Independent instrumental variables significantly associated with sedentary behaviors (p < 5 × 10−8) are obtained from a genome‐wide association study (GWAS) of 422,218 individuals, and Frailty Index (FI) are derived from the latest GWAS dataset of 175,226 individuals. MR analysis is conducted using inverse variance weighting, MR‐Egger, weighted median, simple mode, and weighted mode, supplemented by MRAPSS. Univariate MR revealed that sedentary behaviors such as watching television increased the risk of frailty (OR, 1.271; 95% CI: 1.202‐1.345; p = 6.952 × 10−17), as sedentary driving behaviors are done (OR, 1.436; 95% CI: 1.026‐2.011; p = 0.035). Further validation through APSS, taking into account cryptic relatedness, stratification, and sample overlap, maintained the association between television viewing and increased frailty risk (OR, 1.394; 95% CI: 1.266‐1.534; p = 1.143 × 10−11), while the association with driving dissipated. In multivariate inverse variance weighted (IVW) analysis, after adjusting for C‐reactive protein (CRP) levels, television Sedentary behavior (SB) inversely affected frailty (OR, 0.782; 95% CI: 0.724‐0.845; p = 4.820 × 10−10). This study indicates that televisio SB significantly increases the risk of frailty, suggesting potential biological heterogeneity behind specific sedentary activities. This process may interact with inflammation, influencing the development of frailty.

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A genome‐wide association study of the frailty index highlights brain pathways in ageing

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 160 publications

References 62 publications

Genetically predicted frailty index and risk of stroke and Alzheimer's disease

Genetically predicted frailty index and risk of stroke and Alzheimer's disease

Frailty in individuals with depression, bipolar disorder and anxiety disorders: longitudinal analyses of all-cause mortality

Modifiable Lifestyle, Sedentary Behaviors and the Risk of Frailty: A Univariate and Multivariate Mendelian Randomization Study

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