Bridging the Gap between Genetic Associations and Drug Discovery with Functional Genomics
The field of human genetics has made remarkable strides in the past 20 years, from the first human genome draft in 2001 to the first fully sequenced human genome in 2022. When the first genome-wide association study (GWAS) linking genetic variations to common complex human disease was completed in the early 2000s, it was hard to imagine that there would be over 6,000 GWAS publications today. Yet for all this progress, there remains a disconnect between genetic associations yielded by GWAS and the mechanisms through which disease develops that are needed for therapeutic discoveries. Much of the challenge lies in identifying the causal variant that drives disease association and, more importantly, the causal genes implicated in an association. Even when the causal genes are mapped, characterizing their functions and dysregulation in disease continues to be a hurdle.
As a computational and translational geneticist at Variant Bio, I have the opportunity to work with a diverse group of scientists taking on this challenge. Our team includes anthropologists, engineers, and bioinformaticians, as well as computational and molecular geneticists, disease biologists, chemists, and clinicians. By involving people of different backgrounds in study design, data analysis, and results interpretation, we are working to advance therapeutic discovery rooted in human genetics.
The central tenet of molecular biology states that genetic variations can influence how much a gene is expressed or functions in a cell and organism, which in turn influences the protein products that carry out cellular functions.¹ To extend this tenet, other biomarkers, endophenotypes, or other risk factors (e.g. high blood lipid) beyond protein changes can influence disease outcome (e.g. cardiovascular disease).² At Variant Bio, we investigate multi-omics (multiple types of molecular data) and phenotypes to improve our understanding of disease development and progression. My role in functional genomics is to connect these data types. For instance, I explore how a genomic change at the nucleotide level can lead to a change in gene, protein, or metabolite amount and influence disease risk outcome. The path from variant to gene to function requires multi-disciplinary expertise and cross-functional collaboration within and across organizations, as thoughtfully outlined and discussed by many pioneers in the field.³
But what does functional genomics consist of exactly? My work largely comprises three main areas: 1) computationally assessing multi-omics data quality and its relationships with genetic variations and disease (data quality control and associations), 2) connecting statistical results across layers of omics data to help recapitulate disease processes (results integration), and 3) working with molecular and disease biologists to prioritize genes with actionable insights to identify good targets for drug discovery and development (target identification). What I enjoy the most in my day-to-day work is analyzing multidimensional and unique datasets, working with and learning from team members of diverse expertise to realize the fullest potential of the results, and seeing the translational impact of genetic findings yielded from such analyses. It is personally satisfying to go through the investigative process of why a genetic association matters and, more importantly, how it can change what we know about disease biology.
Given the interdisciplinary nature of our work, collaboration and partnerships are at the front and center of Variant Bio’s approach. Beyond clear communication and openness to learn from one another, this requires deep understanding, acceptance, and the ability to speak each other’s languages in order to truly feel we belong and can thrive and excel. Leadership and team members are as serious about fostering diversity, equity, and inclusion internally as they are about carrying out ethical research around the world. Such an approach sets us up for success through a wide array of educational resources, workshops, and discussions on important topics in order to raise our awareness and enable us to do right by colleagues and partner communities.
These are just some of the many reasons why I am excited to do what I love scientifically while contributing to global health impacts and bringing my true and best self to work.
References:
- Crick. On protein synthesis. Symp Soc Exp Biol 12:138–63 (1958).
- Steuer et al. Metabolomic Strategies in Biomarker Research–New Approach for Indirect Identification of Drug Consumption and Sample Manipulation in Clinical and Forensic Toxicology? Front Chem 7:319 (2019). doi: 10.3389/fchem.2019.00319.
- Lichou & Trynka. Functional studies of GWAS variants are gaining momentum. Nat Comm 11:6283 (2020). doi: 10.1038/s41467–020–20188-y.
