The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities
Eric Venner(Baylor College of Medicine), Karynne Patterson(University of Washington), Divya Kalra(Baylor College of Medicine), Marsha M. Wheeler(University of Washington), Yi–Ju Chen(Baylor College of Medicine), Sara E. Kalla(Baylor College of Medicine), Bo Yuan(Baylor College of Medicine), Jason H. Karnes(University of Arizona), Kimberly Walker(Baylor College of Medicine), Joshua D. Smith(University of Washington), Sean McGee(University of Washington), Aparna Radhakrishnan(University of Washington), Andrew Haddad(University of Pittsburgh), Philip E. Empey(University of Pittsburgh), Qiaoyan Wang(Baylor College of Medicine), Lee Lichtenstein(Broad Institute), Diana Toledo(Broad Institute), Gail P. Jarvik(University of Washington), Anjene Musick(National Institutes of Health), Richard A. Gibbs(Baylor College of Medicine), Brian Ahmedani(Henry Ford Health System), Christine D. Cole Johnson(Henry Ford Health System), Habib Ahsan(University of Chicago Medical Center), Hoda Anton-Culver(University of California, Irvine), Eric Topol(Scripps Research Institute), Katie Baca-Motes(Scripps Research Institute), Julia Moore-Vogel(Scripps Research Institute), Praduman Jain, Mark Begale, Neeta Jain, David Klein, Scott Sutherland, Bruce Korf(University of Alabama at Birmingham), Beth Lewis(University of Alabama at Birmingham), Ali G. Gharavi(Columbia University), George Hripcsak(Columbia University), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Scott Joseph Hebbring(Marshfield Clinic), Elizabeth Burnside(University of Wisconsin–Madison), Dorothy Farrar-Edwards(University of Wisconsin–Madison), Amy Taylor(Community Health Center), Liliana Lombardi Desa, Steve Thibodeau(Mayo Clinic), Mine Cicek(Mayo Clinic), Eric Schlueter(Prisma Health), Beverly Wilson Holmes(Prisma Health), Martha Daviglus(University of Illinois Chicago), Paul Harris(Vanderbilt University Medical Center), Consuelo Wilkins(Vanderbilt University Medical Center), Dan Roden(Vanderbilt University Medical Center), Kim Doheny(Johns Hopkins University), Evan Eichler(University of Washington), Gail Jarvik(University of Washington), Gretchen Funk, Anthony Philippakis(Broad Institute), Heidi Rehm(Broad Institute), Stacey Gabriel(Broad Institute), Richard Gibbs(Baylor College of Medicine), Edgar M. Gil Rico(National Alliance for Hispanic Health), David Glazer, Jessica Burke(Mitre (United States)), Philip Greenland(Northwestern University), Elizabeth Shenkman(University of Florida), William R. Hogan(University of Florida), Priscilla Igho-Pemu(Morehouse School of Medicine), Elizabeth W. Karlson(Mass General Brigham), Jordan Smoller(Mass General Brigham), Shawn N. Murphy(Mass General Brigham), Margaret Elizabeth Ross(Cornell University), Rainu Kaushal(Cornell University), Eboni Winford(Cherokee Nation), Vik Kheterpal(CareEvolution (United States)), Francisco A. Moreno(University of Arizona), Cheryl Thomas(Delta Air Lines (United States)), Mitchell Lunn(Stanford University), Juno Obedin-Maliver(Stanford University), Oscar Marroquin(University of Pittsburgh), Shyam Visweswaran(University of Pittsburgh), Steven Reis(University of Pittsburgh), Patrick McGovern, Gregory Talavera(San Ysidro Health), George T. O’Connor(Boston Medical Center), Lucila Ohno-Machado(University of California San Diego), Fornessa Randal(Asian Health Coalition), Andreas A. Theodorou(Banner Health), Eric Reiman(Banner Health), Mercedita Roxas-Murray, Louisa Stark(University of Utah), Ronnie Tepp(HCM Strategists (United States)), Alicia Zhou(Color (United States)), Scott Topper(Color (United States)), Rhonda Trousdale(New York City Health and Hospitals Corporation), Phil Tsao(The Coordinating Center), Scott T. Weiss(Brigham and Women's Hospital), Jeffrey Whittle(Medical College of Wisconsin), Stephan Zuchner(University of Miami), Olveen Carrasquillo(University of Miami), Megan Lewis(RTI International), Jen Uhrig(RTI International), May Okihiro(Waianae Coast Comprehensive Health Center), Maria Argos(University of Illinois Chicago), Brisa Aschebook-Kilfoy(University of Illinois Chicago), Laura Bartlett(United States National Library of Medicine), Roberta Carlin, Elizabeth Cohn(Hunter College), Vivian Colon-Lopez(University of Puerto Rico System), Karl Cooper, Linda Cottler, Errol Crook(University of South Alabama), Elizabeth Culler, Charles Drum, Milton Eder, Mark Edmunds, Rachel Everhart(Denver Health Medical Center), Adolph Falcon(National Alliance for Hispanic Health), Becky Fein(Applied Minds (United States)), Zeno Frano(Medical College of Wisconsin), Michael Garrett(Jackson Memorial Hospital), Sandra Halverson, Eileen Handberg(University of Florida), Joyce Ho(Northwestern University), Laura Horne(Applied Minds (United States)), Rosario Isasi(University of Miami), Jessica Isom(Massachusetts General Hospital), Jessica Jarmin(CACI International (United States)), Megan Jula(University of Mary Washington), Royan Kamyar, Frida Kleiman(Hunter College), Isaac Kohane(Harvard University), Babbette Lamarca(Jackson Memorial Hospital), Brendan Lee(Baylor College of Medicine), Niall Lennon(Broad Institute), Dessie Levy(National Capital Baptist Convention), Todd Mahr(Gundersen Health System), Emily Makahi(Waianae Coast Comprehensive Health Center), Vivienne Marshall(South Texas Blood and Tissue Center), Elizabeth Mayer-Davis(University of North Carolina at Chapel Hill), Jacob McCauley(University of Miami), Jeffrey McKinney, David McPherson(The University of Texas Health Science Center at Houston), Robert Meller(Morehouse School of Medicine), Jose Melo(University of Puerto Rico System), David Ming-Hung Lin(Bloodworks Northwest), Michael Minor(National Capital Baptist Convention), Evan Muse(Scripps Research Institute), Kapil Parakh(Fitbit (United States)), Cathryn Peltz-Rauchman(Henry Ford Health System), Linda Perez Laras(Puerto Rico Department of Health), Subhara Raveendran(Patients First), Gail Reilly(Cherokee Nation), Jody Reilly(Quest Diagnostics (United States)), Nelida Rivera(Puerto Rico Department of Health), Laura Rosales(Baylor College of Medicine), Tracie Rosser(Emory University), Linda Salgin(San Ysidro Health), Sherilyn Sawyer, William Simonson, Amy Sitapati(University of California San Diego), Cynthia So-Armah(Massachusetts General Hospital), Gene Stegeman, Christin Suver(Sage Bionetworks), Michael Taitel(Walgreens (United States)), Kyla Taylor(Cherokee Nation), Daniel Hernandez Tinoco(Cherokee Nation), Jason Vassy, Jamie Walz, Preston Watkins(New York City Health and Hospitals Corporation), Blaker Wilkerson(Blue Cross Blue Shield Association), Katrina Yamazaki(Community Health Center), Melissa Basford(Vanderbilt University Medical Center), Amaryllis Silva Boschetti(University of California San Diego), Matthew Breeden(Saint Louis University), Suchitra Chandrasekaran(Emory University), Cheryl Clark(Brigham and Women's Hospital), Kim Enard(Saint Louis University), Yuri Fresko(Quest Diagnostics (United States)), Richard Grucza(Saint Louis University), Robert Kelley(Emory University), Kathleen Keogh, Monica Kraft(Mount Sinai Health System), Christopher Lough, Ted Malmstrom(Saint Louis University), Paul Nemeskal(Massachusetts General Hospital), Matt Pagel(Emory University), Jeffrey Scherrer(Saint Louis University), Sanjay Skukla(Marshfield Clinic), Debra Smith, Bryce Turner(University of Southern California), Miriam Vos(Emory University)
Cited by 50Open Access
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.
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