Imputation provides an opportunity to study filaggrin ( ) null mutations in large population cohorts that lack bespoke genotyping.

BACKGROUND

Null mutations within the filaggrin ( ) gene are established genetic risk factors for atopic dermatitis. Studies of have typically used sequencing or bespoke genotyping. Large-scale population cohorts with genome-wide imputed data offer powerful genetic analysis opportunities, but bespoke genotyping is often not feasible in such studies. Therefore, we aimed to determine the quality of selected null genotype data extracted from genome-wide imputed sources, focussing on UK population data.

METHODS

We compared the allele frequencies of three null mutations that could be detected by imputation (p.Arg501Ter, p.Arg2447Ter and p.Ser3247Ter; commonly referred to as R501X, R2447X and S3247X respectively) in directly genotyped and genome-wide imputed data in the ALSPAC cohort. Logistic regression analysis was used to test the association of atopic dermatitis with imputed and genotyped null mutations in ALSPAC and UK Biobank to investigate the usefulness of imputed data.

RESULTS

The three null mutations appear to be well imputed in datasets that use the Haplotype Reference Consortium (HRC) for imputation (0.3% discordance compared with directly genotyped data). However, a greater proportion of null alleles failed imputation compared to wild-type alleles. Despite the calling of mutations in imputed data being imperfect, they are still strongly associated with atopic dermatitis (p-values between 7x10 and 5x10 in UK Biobank).

CONCLUSIONS

HRC imputed data appears to be adequate for UK population-based genetic analysis of selected null mutations (p.Arg501Ter, p.Arg2447Ter and p.Ser3247Ter).