Research Question: Are there X chromosome (Xchr) loci that confer parent-of-origin specific diabetes mellitus (DM) risk?
Objective: Identify Xchr loci that are likely parent-of-origin hotspots impacting glycemia.
Scientific Rationale: Considerable research suggests that parent-of-origin effects exist for a spectrum of complex traits, including type 2 DM. Studies have historically required genetic data from related individuals to detect variants demonstrating parent-of-origin effects, but this significantly diminishes power and limits genome-wide discovery of the modest effects expected for complex traits. As such, researchers have transitioned to detecting these in GWAS-scale cohorts. However, the Xchr has not been studied in this regard. As of 2021, the sex chromosomes were still omitted from ~75% of GWAS. It is likely that Xchr parent-of-origin effects could be detected via sex-chromosome inclusive research.
Methods: Our study population will include females from UK Biobank who have fasting glucose, triglycerides, high density lipoprotein, and X chromosome genotyping, as well as relevant covariates available. Individuals with putative sex chromosome aneuploidy or have inconsistent sex (reported sex does not match genetic sex) will be excluded. Genotypes will be phased using SHAPEIT3. Imputation will be performed with IMPUTE2using reference data from the Haplotype Reference Consortium and UK10K. We will phase and impute the pseudoautosomal (PAR) regions and non-PAR regions independently as previously described. Genotype variants with call rate > 95%, Hardy-Weinberg equilibrium p-value 0.001 will be retained for parent-of-origin analysis with POIROT. Imputed Xchr variants with a minor allele frequency > 0.001 and INFO score >/=0.3 will also be included.
Primary outcome: Xchr SNPs with a POIROT p-value below a Bonferroni-adjusted p-value for the # Xchr SNPs used
