SURFBAT: a surrogate family based association test building on large imputation reference panels
Authors: Herzig Anthony F , Rubinacci Simone , Marenne Gaëlle , Perdry Hervé ,   FrEx Consortium, Génin Emmanuelle , Campion Dominique , Dartigues Jean-François , Deleuze Jean-François , Lambert Jean-Charles , Redon Richard , Ludwig Thomas , Grenier-Boley Benjamin , Letort Sébastien , Lindenbaum Pierre , Meyer Vincent , Quenez Olivier , Dina Christian , Bellenguez Céline , Charbonnier-Le Clézio Camille , Giemza Joanna , Chatel Stéphanie , Férec Claude , Marec Hervé Le , Letenneur Luc , Nicolas Gaël , Rouault Karen , Bacq Delphine , Boland Anne , Lechner Doris ,   FranceGenRef Consortium, Deleuze Jean-François , Génin Emmanuelle , Redon Richard , Adjou Chantal , Chatel Stéphanie , Férec Claude , Goldberg Marcel , Halbout Philippe-Antoine , Marec Hervé Le , L’Helgouach David , Rouault Karen , Schott Jean-Jacques , Vogelsperger Anne , Zins Marie , Bacq Delphine , Blanché Hélène , Boland Anne , Olaso Robert , Lindenbaum Pierre , Ludwig Thomas , Meyer Vincent , Sandron Florian , Delafoy Damien , Velo-Suárez Lourdes , Alves Isabel , Bocher Ozvan , Dina Christian , Herzig Anthony F , Karakachoff Matilde , Marenne Gaëlle , Pierre Aude Saint , Geoffroy Véronique , Deleuze Jean-François , Dina Christian , Barc Julien , Redon Richard , Delaneau Olivier , Génin Emmanuelle 
Published: December 2024

Abstract
Genotype–phenotype association tests are typically adjusted for population stratification using principal components that are estimated genome-wide. This lacks resolution when analyzing populations with fine structure and/or individuals with fine levels of admixture. This can affect power and precision, and is a particularly relevant consideration when control individuals are recruited using geographic selection criteria. Such is the case in France where we have recently created reference panels of individuals anchored to different geographic regions. To make correct comparisons against case groups, who would likely be gathered from large urban areas, new methods are needed. We present SURFBAT (a surrogate family based association test), which performs an approximation of the transmission-disequilibrium test. Our method hinges on the application of genotype imputation algorithms to match similar haplotypes between the case and control groups. This permits us to approximate local ancestry informed posterior probabilities of un-transmitted parental alleles of each case individual. This is achieved by assuming haplotypes from the imputation panel are well-matched for ancestry with the case individuals. When the first haplotype of an individual from the imputation panel matches that of a case individual, it is assumed that the second haplotype of the same reference individual can be used as a locally ancestry matched control haplotype and to approximately impute un-transmitted parental alleles. SURFBAT provides an association test that is inherently robust to fine-scale population stratification and opens up the possibility of efficiently using large imputation reference panels as control groups for association testing. In contrast to other methods for association testing that incorporate local-ancestry inference, SURFBAT does not require a set of ancestry groups to be defined, nor for local ancestry to be explicitly estimated. We demonstrate the interest of our tool on simulated datasets, as well as on a real-data example for a group of case individuals affected by Brugada syndrome.