Trans gene regulation and its role in complex disease genetics
The majority of GWAS variants are located in non-coding regions of the genome, indicating that these variants affect the phenotypic outcome through regulating expression levels of genes. Trans gene regulation, which is the regulation of gene expression by variants that are far away (mega-bases away or on different chromosomes), is a major component of gene regulation. It was estimated that trans regulation explains more than 2X the variance of gene expression than cis regulation. More importantly, trans effects manifested in gene regulatory network explain the highly polygenic architecture of complex traits. It was further estimated that more than 70% of trait variance comes from trans regulation of core genes. However, to date, very little is known about trans regulation, due to experimental and statistical challenges. My lab is interested in studying trans- gene regulation in the following three areas:
- Use of statistical methods to produce high-quality and comprehensive maps of trans-QTLs in human cell-types. This area involves major effort in developing new statistical methods to increase the power of trans-QTL mapping, and the goal is the produce the most comprehensive maps of trans-QTLs in human cell types.
- In-depth characterization of trans-regulatory mechanisms in human cell-types. The regulatory mechanism of nearly half of the trans-eQTLs may not be through cis-regulation of gene expression levels, but by other processes such as altering coding sequences or through undetermined molecular intermediates. A detailed accounting of the mechanisms by which genetic effects propagate through gene regulatory networks and biological pathways will greatly help generate hypotheses and functional follow-up for individual GWAS loci.
- Disease genes discovery with high-quality trans-eQTLs. As GWAS variants are highly enriched in cis-eQTLs, a widely used strategy to identify disease genes relies on the co-localization of cis-eQTL and GWAS variants. Though it is a reasonable and promising approach40,46, solely relying on cis-eQTLs limits our chances of finding causal genes. Given the recent findings on the importance of trans regulation on disease genetics (see Overall background and significance), we propose to develop new methods that use trans-eQTLs to map disease genes.
Polygenic selection and polygenic risk scores of complex traits and diseases
Due to different linkage disequilibrium (LD), minor allele frequency (MAF) patterns, stratification, and other reasons, polygenic risk scores (PRS) are not easily portable across populations of different ancestries. We are interested in i) understanding the sharing of causal effects across different populations and ii) developing new methods that estimate pseudo-causal effects that allow better prediction of PRS across populations.