Shared genetic influence on frailty and chronic widespread pain: a study from TwinsUK

Abstract

Introductionfrailty is an increased vulnerability to adverse health outcomes, across multiple physiological systems, with both environmental and genetic drivers. The two most commonly used measures are Rockwood’s frailty index (FI) and Fried’s frailty phenotype (FP).Material and methodsthe present study included 3626 individuals from the TwinsUK Adult Twin Registry. We used the classical twin model to determine whether FI and FP share the same latent aetiological factors. We also investigated the relationship between frailty and chronic widespread musculoskeletal pain (CWP), another holistic age-related condition with significant clinical impact.ResultsFP and FI shared underlying genetic and environmental aetiology. CWP was associated with both frailty measures, and health deficits appeared to mediate the relationship between phenotypic frailty and pain. Latent genetic factors underpinning CWP were shared with frailty. While frailty was increased in the twins reporting pain, co-twin regression analysis indicated that the relationship between CWP and frailty is reduced after accounting for shared genetic and environmental factors.Conclusionsboth measures of frailty tap the same root causes, thus this work helps unify frailty research. We confirmed a strong association between CWP and frailty, and showed a large and significant shared genetic aetiology of both phenomena. Our findings argue against pain being a significant causative factor in the development of frailty, favouring common causation. This study highlights the need to manage CWP in frail individuals and undertake a Comprehensive Geriatric Assessment in individuals presenting with CWP. Finally, the search for genetic factors underpinning CWP and frailty could be aided by integrating measures of pain and frailty.

A Genome-Wide Association Study of the Frailty Index Highlights Synaptic Pathways in Aging

“…Our SNP-based heritability estimate of 14% for the FI was slightly lower than previous family-or twin-based estimates between 19 and 45% (Livshits, Lochlainn, et al 2018) (Murabito et al 2012) (Young et al 2016). This is expected as this SNP-based estimate does not include rare, structural, non-additive, or non-autosomal genetic influences.…”

“…The mechanisms underlying frailty are likely multifactorial but not well understood. Studies have suggested a genetic basis, with heritability estimates between 19 and 45% (Livshits, Lochlainn, et al 2018) (Murabito et al 2012) (Young et al 2016). Candidate gene association studies for frailty have suggested the involvement of genes in inflammatory pathways (Viña et al 2016), including tumour necrosis factor (Mekli et al 2016) and interleukin-18 (Mekli et al 2015).…”

Physical frailty and decline in general and specific cognitive abilities: the Lothian Birth Cohort 1936

“…Another area for exploration is whether genetic susceptibility to physical frailty is associated with differences in cognitive ageing. Twin studies have reported heritability estimates for physical frailty of around 40%,30 31 however, in the small cohorts studied to date, no genetic variant has been consistently associated with this phenotype. Meta-analysis of genome-wide association studies of physical frailty should throw light on which genetic variants confer susceptibility, allowing the construction of polygenic risk scores.…”

Multi-OMICS analyses of frailty and chronic widespread musculoskeletal pain suggest involvement of shared neurological pathways

“…The biological mechanisms underlying frailty have been extensively studied in recent years. 15 , 26 We have shown that interindividual variation of frailty scores significantly depends on genetic factors, which explain 34% of their variation. We also found that chronic widespread musculoskeletal pain (CWP)—another prevalent age-related condition—is significantly associated with the Rockwood Frailty Index (FI), and that this association is caused by shared genetic and common environmental factors.…”