The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities
Authors: Venner Eric , Patterson Karynne , Kalra Divya , Wheeler Marsha M. , Chen Yi-Ju , Kalla Sara E. , Yuan Bo , Karnes Jason H. , Walker Kimberly , Smith Joshua D. , McGee Sean , Radhakrishnan Aparna , Haddad Andrew , Empey Philip E. , Wang Qiaoyan , Lichtenstein Lee , Toledo Diana , Jarvik Gail , Musick Anjene , Gibbs Richard A. ,   the All of Us Research Program Investigators, Ahmedani Brian , Johnson Christine D. Cole , Ahsan Habib , Anton-Culver Hoda , Topol Eric , Baca-Motes Katie , Moore-Vogel Julia , Jain Praduman , Begale Mark , Jain Neeta , Klein David , Sutherland Scott , Korf Bruce , Lewis Beth , Gharavi Ali G. , Hripcsak George , Boerwinkle Eric , Hebbring Scott Joseph , Burnside Elizabeth , Farrar-Edwards Dorothy , Taylor Amy , Desa Liliana Lombardi , Thibodeau Steve , Cicek Mine , Schlueter Eric , Holmes Beverly Wilson , Daviglus Martha , Harris Paul , Wilkins Consuelo , Dan Roden  , Doheny Kim , Eichler Evan , Jarvik Gail , Funk Gretchen , Philippakis Anthony , Rehm Heidi , Gabriel Stacey , Gibbs Richard , Rico Edgar M. Gil , Glazer David , Burke Jessica , Greenland Philip , Shenkman Elizabeth , Hogan William R. , Igho-Pemu Priscilla , Karlson Elizabeth W. , Smoller Jordan , Murphy Shawn N. , Ross Margaret Elizabeth , Kaushal Rainu , Winford Eboni , Kheterpal Vik , Moreno Francisco A. , Thomas Cheryl , Lunn Mitchell , Obedin-Maliver Juno , Marroquin Oscar , Visweswaran Shyam , Reis Steven , McGovern Patrick , Talavera Gregory , O’Connor George T. , Ohno-Machado Lucila , Randal Fornessa , Theodorou Andreas A. , Reiman Eric , Roxas-Murray Mercedita , Stark Louisa , Tepp Ronnie , Zhou Alicia , Topper Scott , Trousdale Rhonda , Tsao Phil , Weiss Scott T. , Whittle Jeffrey , Zuchner Stephan , Carrasquillo Olveen , Lewis Megan , Uhrig Jen , Okihiro May , Argos Maria , Aschebook-Kilfoy Brisa , Bartlett Laura , Carlin Roberta , Cohn Elizabeth , Colon-Lopez Vivian , Cooper Karl , Cottler Linda , Crook Errol , Culler Elizabeth , Drum Charles , Eder Milton , Edmunds Mark , Everhart Rachel , Falcon Adolph , Fein Becky , Frano Zeno , Garrett Michael , Halverson Sandra , Handberg Eileen , Ho Joyce , Horne Laura , Isasi Rosario , Isom Jessica , Jarmin Jessica , Jula Megan , Kamyar Royan , Kleiman Frida , Kohane Isaac , Lamarca Babbette , Lee Brendan , Lennon Niall , Levy Dessie , Mahr Todd , Makahi Emily , Marshall Vivienne , Mayer-Davis Elizabeth , McCauley Jacob , McKinney Jeffrey , McPherson David , Meller Robert , Melo Jose , Lin David Ming-Hung , Minor Michael , Muse Evan , Parakh Kapil , Peltz-Rauchman Cathryn , Laras Linda Perez , Raveendran Subhara , Reilly Gail , Reilly Jody , Rivera Nelida , Rosales Laura , Rosser Tracie , Salgin Linda , Sawyer Sherilyn , Simonson William , Sitapati Amy , So-Armah Cynthia , Stegeman Gene , Suver Christin , Taitel Michael , Taylor Kyla , Tinoco Daniel Hernandez , Vassy Jason , Walz Jamie , Watkins Preston , Wilkerson Blaker , Yamazaki Katrina , Basford Melissa , Boschetti Amaryllis Silva , Breeden Matthew , Chandrasekaran Suchitra , Clark Cheryl , Enard Kim , Fresko Yuri , Grucza Richard , Kelley Robert , Keogh Kathleen , Kraft Monica , Lough Christopher , Malmstrom Ted , Nemeskal Paul , Pagel Matt , Scherrer Jeffrey , Skukla Sanjay , Smith Debra , Turner Bryce , Vos Miriam 
Published: February 2024

AbstractDisparities 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.