Modeling gene expression on the X chromosome in the brain for transcriptome‐wide association studies

Analysis of sex chromosomes is under‐reported in Alzheimer’s disease (AD) studies. As we gain more knowledge of disease associations and tissue‐specific regulatory effects of autosomal loci, there is a growing interest in building prediction models of gene expression in the brain to model the cumulative functions of non‐coding variants on the sex chromosomes. Transcriptome‐wide Association Studies (TWAS) can identify disease‐associated genes using these prediction models built for specific tissues by integrating genotype, imputed gene expression, and phenotype information. A key challenge of this approach for sex chromosome analysis is how to model copy number differences between males and females: genetic variants on the X chromosome are hemizygous for males, while females are heterozygous or homozygous diploid.