How local reference panels improve imputation in French populations
Abstract
Imputation servers offer the exclusive possibility to harness the largest public reference panels
which have been shown to deliver very high precision in the imputation of European genomes. Many
studies have nonetheless stressed the importance of ‘study specific panels’ (SSPs) as an alternative
and have shown the benefits of combining public reference panels with SSPs. But such combined
approaches are not attainable when using external imputation servers. To investigate how to
confront this challenge, we imputed 550 French individuals using either the University of Michigan
imputation server with the Haplotype Reference Consortium (HRC) panel or an in‑house SSP of 850
whole‑genome sequenced French individuals. With approximate geo‑localization of both our target
and SSP individuals we are able to pinpoint different scenarios where SSP‑based imputation would
be preferred over server‑based imputation or vice‑versa. This is achieved by showing to a high degree
of resolution the importance of the proximity of the reference panel to target individuals; with a
focus on the clear added value of SSPs for estimating haplotype phase and for the imputation of rare
variants (minor allele‑frequency below 0.01). Such benefits were most evident for individuals from
the same geographical regions in France as the SSP individuals. Overall, only 42.3% of all 125,442
variants evaluated were better imputed with an SSP from France compared to an external reference
panel, however this rises to 58.1% for individuals from geographic regions well covered by the SSP.
By investigating haplotype sharing and population fine‑structure in France, we show the importance
of including SSP haplotypes for imputation but also that they should ideally be combined with large
public panels. In the absence of the unattainable results from a combined panel of the HRC and our
French SSP, we put forward a pragmatic solution where server‑based and SSP‑based imputation
outcomes can be combined based on comparing posterior genotype probabilities. We show that such
an approach can give a level of imputation accuracy in excess of what could be achieved with either
strategy alone. The results presented provide detailed insights into the accuracy of imputation that
should be expected from different strategies for European populations.
Domains
Life Sciences [q-bio]| Origin | Publisher files allowed on an open archive |
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