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Title: Advances and challenges in X chromosome-aware whole genome genetic studies Authors:  Lei Sun - University of Toronto (Canada) [presenting]
Bo Chen - University of Toronto (Canada)
Radu Craiu - University of Toronto (Canada)
Wei Deng - McMaster University (Canada)
Lloyd Elliott - Simon Fraser University (Canada)
Elika Garg - Simon Fraser University (Canada)
Andrew Paterson - Hospital for Sick Children (Canada)
Lisa Strug - University of Toronto (Canada)
Zhong Wang - Fudan University (Canada)
Lin Zhang - University of Toronto (Canada)
Abstract: The inclusion of the X chromosome (Xchr) in genome-wide association studies is known to be difficult due to multiple analytical challenges, particularly the uncertainty of X-inactivation, where one of the two Xchrs in a female may be randomly or preferentially selected to have no effect (i.e. dosage compensation), and there is also the possibility of no X-inactivation (i.e. X-inactivation escape). To date, only ~0.5\% of associated SNPs in the NHGRI-EBI GWAS catalog is on the Xchr, a 10-fold paucity compared to the autosomes. We will first present an Xchr association method that is robust to X-inactivation uncertainty and easy-to-implement, and compare it with other methods that have focused on X-inactivation. We will then present evidence for the previously under-appreciated phenomenon of sex differences in minor allele frequency (sdMAF), from a recent analysis of the 1000 Genomes Project data. sdMAF may affect the validity and power of the existing X-inactivation-focused association methods, as well as our current understanding of Hardy-Weinberg equilibrium and linkage disequilibrium on the Xchr. We will also discuss the relevance of these results to the Genetic Epidemiology Committee analysis of the CGEn COVID-19 Host Genome Sequence Project data. Finally, as GWAS is the basis for polygenic risk score (PRS)-based disease prediction, we will discuss opportunities and challenges facing the Xchr-inclusive PRS research.