Inside AJHG: A Chat with Mark McCarthy

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Mark McCarthy, MD

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 Mark McCarthy (@markmccarthyoxf) to discuss his paper “A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression.”

AJHG: What prompted you to start working on this project? 

Mark: One of the key challenges in the follow up of the association signals delivered by GWAS – most of which map to noncoding sequence – lies in identifying the gene through which the causal variant is likely to be acting to mediate the phenotype of interest. There are a number of approaches that are widely used to gain clues to the identity of these effectors – including cis-eQTL mapping and Hi-C related methods – but there have been relatively few attempts to work out how reliable these methods might be. Part of the challenge lies in finding “truth sets”, that is, examples of genes that can be confidently and causally linked to both regulatory GWAS variants, and to trait outcomes, and which can be used to evaluate the performance of such approaches. The metabolomics GWAS hits we used here fulfilled this purpose and allowed us to see how often cis-eQTL approaches to effector identification were likely to be delivering the right result.

AJHG: What about this paper/project most excites you? 

Mark:  I think this paper – along with others that have appeared from colleagues whilst we were working on this – reinforces the notion that linking regulatory variants to their downstream effectors, and demonstrating that those effectors are actually causal for disease, is really hard. No single approach is likely to deliver reliable results, and we should be extremely wary of inference that is not based on triangulation across multiple sources of data.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Mark: We have come to realize that it is not enough – from the perspective of defining disease mechanisms – to show that a given regulatory GWAS variant interacts with the promoter of a given nearby gene to influence its expression. Even when we have confidence in those interactions – gathered from cis-eQTL colocalization, DNA proximity assays, or single nuclear ATAC-Seq co-accessibility for example – we cannot assume that the gene concerned is causal. There’s a lot of molecular pleiotropy, and many regulatory variants will interact with multiple nearby genes across a range of cell-types and conditions. At the end of the day, these genomic methods can provide hypotheses about causation, but ultimately “proof” requires demonstration that perturbation of the expression or function of the gene concerned results in a phenotypic effect that is consistent with disease biology. That could come from finding a coding variant in humans that recapitulates the phenotype, or it may require the generation of novel mutations in cellular or animal models.

AJHG: What advice do you have for trainees/young scientists?

Mark: Be clear about your goals, and seek out the group who will help you achieve them.

AJHG: And for fun, tell us something about your life outside of the lab.

Mark: Last summer, I moved from the UK to take up a position at Genentech near San Francisco. There were many reasons why I made the move, and mostly things have played out as I expected. But there have been some unexpected pleasures too: serious hills to climb on my roadbike, watching Liverpool (Football Club) live on the TV over breakfast at the weekend, the ballet of professional basketball, driving for four months before I had to work out where my windscreen wipers were, and the beauty of the Pacific coast.

Mark McCarthy, MD is Senior Director and Staff Scientist, Human Genetics at Genentech. He has been a member of ASHG since 2013.

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