Posted By: Kylee Spencer, PhD, Assistant Editor, AJHG
Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Heather to discuss her recent paper “Transcriptome-wide association study of the plasma proteome reveals cis and trans regulatory mechanisms underlying complex traits.”
KS: What motivated you to start working on this project?
HW: We know from eQTL studies that trans-acting loci tend to have smaller effect sizes than cis-acting loci. By aggregating cis-acting effects into one predicted expression level, as is done in the TWAS method PrediXcan, we had previously shown more power to detect trans-acting effects on gene expression than in traditional SNP eQTL studies. With plasma proteomics data becoming more widely available, we were curious about what we could learn by testing genetically regulated expression for association with plasma protein levels across prediction models trained in 49 tissues.
KS: What about this paper/project most excites you?
HW: A key finding is that associations between predicted mRNA transcripts across diverse tissues and the plasma protein encoded by the same gene, what we call cis-same in the paper, are more likely to replicate than other transcript-protein pairs, including nearby genes, what we call cis-different. In many tissues, we estimated a true positive rate of nearly 1 for the cis-same replication study results, indicating a strong correlation between genetically regulated gene expression levels and observed protein levels. This is in contrast with many studies that have shown a poor correlation between transcript and protein levels of the same underlying gene.
KS: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
HW: We also show the heritable component of gene expression more strongly correlates with protein levels than total observed expression, which includes genetic and environmental variation, and this genetically regulated component is therefore more useful in uncovering the functional mechanisms of SNPs associated with complex traits. More proteomics data in different cellular contexts will help identify additional causal mechanisms underlying GWAS associations. How the genetic effects interact with the environment is still a challenging question to answer and an important next step for the community to pursue.
KS: What advice do you have for trainees/young scientists?
HW: This work would not have been possible without collaboration. It’s important to find collaborators who are there when you need them for advice but are also willing to let you do your own thing. You want to be working “with” others not “for” others. I’ve been collaborating with Haky Im and Ani Manichaikul for years now and they help make doing this work fun and rewarding! I’d also like to thank Jerry Rotter for answering my cold email years ago to chat about an idea I had for combining their MESA data in a new way. My initial collaboration with MESA has led to many new projects since and I am most grateful.
KS: And for fun, tell us something about your life outside of the lab.
HW: When I’m not doing research, teaching or other professoring duties, I’m usually hanging out with my family. My daughter and I like to rate trendy restaurants, explore museums, and attend Sky and Sox games in Chicago. I like watching basketball and baseball more than she does, but she gets her pick of snacks, so it’s a win-win!