The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities
Eric Venner, Karynne Patterson, Divya Kalra, Marsha M. Wheeler, Yi–Ju Chen, Sara E. Kalla, Bo Yuan, Jason H. Karnes, Kimberly Walker, Joshua D. Smith, Sean McGee, Aparna Radhakrishnan, Andrew Haddad, Philip E. Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail P. Jarvik, Anjene Musick, Richard A. Gibbs, Brian Ahmedani, Christine D. Cole Johnson, Habib Ahsan, Hoda Anton-Culver, Eric Topol, Katie Baca-Motes, Julia Moore-Vogel, Praduman Jain, Mark Begale, Neeta Jain, David Klein, Scott Sutherland, Bruce Korf, Beth Lewis, Ali G. Gharavi, George Hripcsak, Eric Boerwinkle, Scott Joseph Hebbring, Elizabeth Burnside, Dorothy Farrar-Edwards, Amy Taylor, Liliana Lombardi Desa, Steve Thibodeau, Mine Cicek, Eric Schlueter, Beverly Wilson Holmes, Martha Daviglus, Paul Harris, Consuelo Wilkins, Dan Roden, Kim Doheny, Evan Eichler, Gail Jarvik, Gretchen Funk, Anthony Philippakis, Heidi Rehm, Stacey Gabriel, Richard Gibbs, Edgar M. Gil Rico, David Glazer, Jessica Burke, Philip Greenland, Elizabeth Shenkman, William R. Hogan, Priscilla Igho-Pemu, Elizabeth W. Karlson, Jordan Smoller, Shawn N. Murphy, Margaret Elizabeth Ross, Rainu Kaushal, Eboni Winford, Vik Kheterpal, Francisco A. Moreno, Cheryl Thomas, Mitchell Lunn, Juno Obedin-Maliver, Oscar Marroquin, Shyam Visweswaran, Steven Reis, Patrick McGovern, Gregory Talavera, George T. O’Connor, Lucila Ohno-Machado, Fornessa Randal, Andreas A. Theodorou, Eric Reiman, Mercedita Roxas-Murray, Louisa Stark, Ronnie Tepp, Alicia Zhou, Scott Topper, Rhonda Trousdale, Phil Tsao, Scott T. Weiss, Jeffrey Whittle, Stephan Zuchner, Olveen Carrasquillo, Megan Lewis, Jen Uhrig, May Okihiro
Abstract
Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.