Nathenael Hundie

Nathenael Hundie, a sophomore computer science major at Harvard College, studied the applicability of the omnigenic model to atrial fibrillation through gene pathway analysis.

As a complex trait, atrial fibrillation (AF) is influenced by many genetic variants. The omnigenic model, a disputed theory regarding complex traits, states that most common variants are associated with AF through peripheral effects on gene regulatory networks, while a smaller number of “core genes” are central to disease pathogenesis. These past nine weeks of BSRP have provided me with such a multifaceted growth experience. I developed significantly as a young scientist through my research project under the support of my research mentors; the project allowed me to learn computational processes to study a condition that genuinely interests me. In addition, I am very grateful to have been under the mentorship of BSRP faculty who have taught me valuable skills in networking, applying to graduate school, and scientific communication. Though I faced numerous challenges during the program, working with others in my cohort allowed me to feel a strong sense of camaraderie that helped me thrive. I am very thankful to have been a part of this cohort with so many exceptional individuals, and I look forward to seeing how we all contribute to the sciences in the coming years.According to this model, we hypothesized that core genes (predicted by rare coding variant associations) should be enriched for common variant associations more so than peripheral genes (predicted by common variant associations) are enriched for rare variant associations. To test this hypothesis, we analyzed the largest available AF GWAS dataset (n = 588,190 mixed-ancestry samples) and the largest available AF rare variant association study (RVAS) dataset (n = 43,139 white, European samples). Preliminary analyses suggest tentative support for our hypothesis: the most significant SNPs in the GWAS are not located near significant RVAS associations, while the most significant RVAS associations lie near GWAS associations to a greater extent. As subsequent hypotheses, we will test (a) whether pathways identified from rare variants are enriched for GWAS associations more so than the converse and (b) whether associated pathways are shared between the GWAS and RVAS to a greater extent than are associated genes. We aim to test these hypotheses by (a) conducting reciprocal enrichment analyses based on the pathways identified from GWAS & RVAS and (b) comparing correlations (between GWAS and RVAS) of pathway associations to those of gene associations. We aim for these tests to evaluate the extent to which the omnigenic model holds for AF; the methods we develop should also be applicable to analyze the omnigenic model for other complex traits.

Project: Evaluating the Extent to Which the Omnigenic Model Applies to Atrial Fibrillation

Mentors: Lokendra Thakur, Jason Flannick, Flannick Lab