Posted By: Sara Cullinan, PhD, Deputy 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 Tom (@iTomRichardson) to discuss his paper “Integrative multiomics analysis highlights immune-cell regulatory mechanisms and shared genetic architecture for 14 immune-associated diseases and cancer outcomes.”
What prompted you to start working on this project?
A critical challenge in genomic medicine is developing insight into the underlying mechanisms that are responsible for association signals detected by genome-wide association studies (GWAS). One of the primary sources of motivation for this project was to harness some of the exciting cell-type specific datasets that are becoming available in larger sample sizes in the field. Specifically, we integrated expression quantitative trait loci (eQTL) data derived from different immune-cell types with findings from GWAS of immune-associated diseases and cancer outcomes. We sought to apply a triangulation framework by analyzing these data using various methodologies, namely Mendelian randomization, genetic colocalization and phenome-wide association studies. This allowed us to investigate evidence from multiple approaches, which all have different strengths and weaknesses. Furthermore, this was a 4-month long rotation project undertaken by lead author Claire Prince, which provided her with an opportunity to gain experience in applying these different techniques before embarking on her main PhD project.
- What about this paper/project most excites you?
I think it’s really exciting that we were able to provide mechanistic insight into cell-type specific effects at GWAS loci in this study. For instance, amongst the key findings in our paper was evidence of a genetically predicted effect of PRKCQ expression on asthma risk which was only identified using data derived from CD4+ T cells, but not when analyzing data from any of the other 17 immune-cell datasets. This result highlights the role that PRKCQ plays in autoimmune disease through T cell activation. I’m also excited by the findings of our phenome-wide analyses as they allowed us to investigate pervasive pleiotropy at trait-associated genetic loci. For example, CASP10 provided evidence of a genetically predicted effect on seven different cancer outcomes, which supports findings from the literature implicating this gene as playing a role in various types of cancer risk.
- Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
There were a huge number of results generated during this project and there simply wasn’t enough space in the paper to discuss them all, which is a testament to the work ethic and ability of lead author Claire. We therefore developed a publicly available web application (located at http://mrcieu.mrsoftware.org/immuno_MR/) which allows users to query all of our findings and visualize them in a gene-centric manner. As such, researchers across the larger human genetics community can readily investigate the cell-type specificity and pleiotropy of genes that they are evaluating in their own research, as well as generate hypotheses for studies into novel genes of interest. We hope this resource helps researchers to prioritize (and deprioritize) genes for future endeavors with the ultimate ambition of improving our understanding of how genes contribute to disease risk.
- What advice do you have for trainees/young scientists?
Early on in my research career I was incredibly fortunate to work with supervisors and mentors who gave me the space to experiment with my own ideas. I would really encourage trainees and young scientists to take advantage of having more time to read papers and to get creative with their own innovative ideas. I’ve always found this to be one of the most fulfilling aspects of a career in research. Like anything, coming up with successful ideas is a skill that you develop with experience, so don’t be afraid to bounce ideas off more senior colleagues who you can learn from. And most of all don’t feel too disheartened if initial ideas don’t work out as well as you’d hoped or if they aren’t well received by fellowship panels. Resilience is a vital quality to have during a career in research, so it’s important that you don’t doubt yourself when there are setbacks along the way.
- And for fun, tell us something about your life outside of the lab.
I’m a bit of a sports fanatic – in particular following my hometown rugby team of Bath who I go to watch with my Dad, as well as watching and playing football (soccer). Whenever possible I also like to get out of the city on weekends to do some hiking around the beautiful countryside we have in the southwest of England. I also really love to travel and attend live music events, which I hope to do more of in the future once pandemic restrictions allow.
Tom Richardson, PhD is Research Fellow at the MRC Integrative Epidemiology Unit and Specialist in Genetics at Novo Nordisk Research Centre Oxford.