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.
