Abstract Background Allergies affect up to 30% of adults and are increasing in prevalence. However, little is known about the genetic aetiology of immediate (type I) and delayed (type IV) immunity underpinning allergic reactions. Delayed hypersensitivity to nickel is the commonest form of contact dermatitis, affecting 17% of women and resulting in considerable occupational disability. The importance of environmental factors in nickel allergy is well established, but the question of this trait's heritability remains unknown. Methods 780 women, comprising 120 monozygotic (MZ) and 270 dizygotic (DZ) twin pairs, were assessed for a 48-h response to nickel patch testing. Associations between nickel sensitivity and the abundance of 401 metabolites were assessed to identify a potential biomarker for this allergic response. A genome-wide association study (GWAS) of the abundance of the top-ranking metabolite was done to ascertain correlations with common genetic variants. Findings A positive patch test to nickel was observed in at least one individual of 34 MZ and 102 DZ twin pairs. The case-wise concordance was approximately 50% for MZs and 30% for DZs, giving an estimated heritability of 54%. Metabolomic profiling showed that the strongest association was with isovalerate (p=1·97 × 10−3 ), a constituent of fatty acid metabolism. The GWAS of the abundance of isovalerate showed that the strongest association was with a single nucleotide polymorphism (SNP) of ANO6 (12q12), rs11183014 (p=1·8 × 10−6 ). There were also suggestive associations with four additional SNPs from ANO6 and a variant of CAMK1D (p<9·5 × 10−6 ). Interpretation Nickel allergy seems to be moderately heritable, and preliminary genetic analyses may suggest functional roles for ANO6 and CAMK1D in this delayed hypersensitivity response. Combined use of metabolomic and genome-wide genotyping data offers great promise in the discovery of novel genetic variants for nickel allergy. Funding King's College London Biomedical Research Centre.