Background Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes including falls, disability and death. The underlying pathophysiological pathways of frailty are not known but the hypothalamic–pituitary–adrenal axis and heightened chronic systemic inflammation appear to be major contributors. Methods We used the English Longitudinal Study of Ageing dataset of 3160 individuals over the age of 50 and assessed their frailty status according to the Fried-criteria. We selected single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways and performed linear association analysis using age and sex as covariates. To support the biological plausibility of any genetic associations, we selected biomarker levels for further analyses to act as potential endophenotypes of our chosen genetic loci. Results The strongest association with frailty was observed in the Tumor Necrosis Factor ( TNF ) (rs1800629, P  = 0.001198, β  = 0.0894) and the Protein Tyrosine Phosphatase, Receptor type, J ( PTPRJ ) (rs1566729, P  = 0.001372, β  = 0.09397) genes. Rs1800629 was significantly associated with decreased levels of high-density lipoprotein (HDL) ( P  = 0.00949) and cholesterol levels ( P  = 0.00315), whereas rs1566729 was associated with increased levels of HDL ( P  = 0.01943). After correcting for multiple testing none of the associations remained significant. Conclusions We provide potential evidence for the involvement of a multifunctional proinflammatory cytokine gene ( TNF ) in the frailty phenotype. The implication of this gene is further supported by association with the endophenotype biomarker results.