Genetic variation of N6-methyladenosine (m6A) RNA modification in immune cells and its contribution to human diseases

Project Summary Identifying risk variants and genes of immune diseases will not only improve our understanding of these diseases, but also point to potential therapeutic targets. Genome-wide association studies (GWAS) are commonly used to study complex diseases, and have been highly successful in a range of disorders, for instance, more than 200 loci have been associated with the risk of asthma. Nevertheless, to translate these associations to mechanistic understanding has been difficult, largely because most of the trait-associated variants are located in noncoding regions with unknown functions. Current work has often been focused on the variants in enhancer regions that may affect gene expression, yet growing evidence suggest that other mechanisms, particularly those regulate RNA processing, may also be important. The goal of this project is to improve our understanding of functions of genetic variants by studying their effects on N6-methyladenosine modification (m6A) of RNA molecules. M6A modification is a relatively new, yet important mechanism of regulating RNA processing, including splicing, degradation, intracellular transport and translation. Despite the widely accepted function of m6A at the molecular level, its contribution to genetics of human disorders is largely unknown. Our recent work on m6A-modifying variants, called m6A-QTLs, in a human B cell line, show shat these m6A-QTLs are enriched with GWAS-detected variants of immune-related traits, and their effects are largely independent of those variants acting on gene expression or splicing, representing a novel path from genetic to phenotypic variations. We propose to extend this work in several directions. (1) We will map m6A-QTLs on mRNAs in several major immune cell types (B, CD4 and CD8 T, NK and monocytes) from human blood, in both resting and immune-stimulated conditions. This study will map many cell-type and response-specific m6A-QTLs that would be missed in a single cell type or condition. (2) We will integrate these resources with GWAS data to identify specific m6A sites and genes that may play important roles in immune phenotypes. This analysis will employ a novel statistical method that improves the power of detecting m6A sites and genes with causal effects. (3) A recently discovered role of m6A is regulation of chromatin-associated RNAs, especially those with regulatory functions (carRNAs), such as enhancer RNAs and repeat-derived RNAs. We will also identify m6A-QTLs of these carRNAs in human T cells, and study their contribution to human immune phenotypes.