How local reference panels improve imputation in French populations
Authors: Herzig Anthony F. , Velo‐Suárez Lourdes ,   The FrEx Consortium,   Principal Investigators, Campion Dominique , Dartigues Jean-François , Lambert Jean-Charles ,   Collaborators,   Bioinformatics, Ludwig Thomas , Grenier-Boley Benjamin , Letort Sébastien , Lindenbaum Pierre , Meyer Vincent , Quenez Olivier ,   Statistical genetics, Bellenguez Céline , Clézio Camille Charbonnier-Le , Giemza Joanna ,   Data collection, Chatel Stéphanie , Férec Claude , Le Marec Hervé , Letenneur Luc , Nicolas Gaël , Rouault Karen ,   Sequencing, Bacq Delphine , Boland Anne , Lechner Doris ,   The FranceGenRef Consortium,   Principal Investigators,   Collaborators,   Data collection, Adjou Chantal , Chatel Stéphanie , Férec Claude , Goldberg Marcel , Halbout Philippe-Antoine , Le Marec Hervé , L’Helgouach David , Rouault Karen , Schott Jean-Jacques , Vogelsperger Anne , Zins Marie ,   Sample preparation/sequencing, Bacq Delphine , Blanché Hélène , Boland Anne , Olaso Robert ,   Bioinformatics, Lindenbaum Pierre , Ludwig Thomas , Meyer Vincent , Sandron Florian , Delafoy Damien , Velo-Suárez Lourdes ,   Statistical Genetics, Alves Isabel , Bocher Ozvan , Herzig Anthony F. , Karakachoff Matilde , Marenne Gaëlle , Pierre Aude Saint , Geoffroy Véronique , Dina Christian , Redon Richard , Deleuze Jean-François , Génin Emmanuelle 
Published: January 2024

AbstractImputation 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.