X chromosome-wide association studies for quantitative trait loci based on the mixture of general pedigrees and additional unrelated individuals.

Genome-wide association studies have successfully identified many genetic variants associated with complex traits. However, most existing methods target autosomes rather than X chromosome, and several existing X chromosome-wide association studies (XWAS) at quantitative trait loci (QTL) largely focus on unrelated individuals, with limited attention to general pedigrees or mixture of general pedigrees and additional unrelated individuals (called the mixed data for brevity). In this study, we propose nine novel methods for XWAS at QTL in the mixed data (${\mathrm{MQX}}_{\mathrm{cat}}$, ${\mathrm{MQZ}}_{\mathrm{max}}$, ${\mathrm{MT}}_{\mathrm{plinkw}}$, ${\mathrm{MT}}_{\mathrm{chenw}}$, $\mathrm{MwM}3\mathrm{VNA}$, ${\mathrm{MQMVX}}_{\mathrm{cat}}$, ${\mathrm{MQMVZ}}_{\mathrm{max}}$, $\mathrm{MpMV}$, and $\mathrm{McMV}$), also applicable to general pedigrees alone. The first four methods test for mean differences across genotypes; the latter four test for differences in both means and variances; $\mathrm{MwM}3\mathrm{VNA}$ tests for variance differences only. All mean-based and mean-variance-based methods incorporate X chromosome inactivation information, and all nine methods consider genetic relatedness in pedigrees. Simulation studies confirm well-controlled type I error rates, and inclusion of pedigrees significantly improves statistical power. Note that there has been no study focusing on X chromosome for the mixed data or general pedigrees from UK Biobank database, so we apply our proposed methods to this dataset, which identify five total cholesterol (TC)-associated and 13 low-density lipoprotein cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs). Linkage disequilibrium (LD) analysis reveals that these SNPs fall into three distinct LD blocks. Functional annotation and gene ontology enrichment analysis reveal 16 and 28 enriched pathways for TC-associated and LDL-C-associated genes, respectively. These methods provide robust and powerful tools for XWAS at QTL in both mixed data and general pedigrees.