Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10<sup>-8</sup> ). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain.