worldwide, have not yet been assessed for population specific GSVs. This also poses a problem for replication – the failure to detect some GSVs in our cohorts may reflect low frequencies in the populations from which they were drawn. Furthermore, although subjects carrying a highly-penetrant causative variant might naïvely be expected to display the phenotype regardless of ethnicity, geographical origin or environmental exposure, we have very little information on the potential for cohort-specific modifiers that can confound that expectation, or on differences in the frequencies or characteristics of rare variants between different populations. As a minimum, therefore, it is essential to include appropriate geographically-matched controls (as was the case in the original reports that are the subject of our replication study).
