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Common and rare variants associated with cardiometabolic traits across 98,622 whole-genome sequences in the All of Us research program

Journal of Human Genetics volume 68, pages 565–570 (2023)Cite this article

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Abstract

All of Us is a biorepository aiming to advance biomedical research by providing various types of data in diverse human populations. Here we present a demonstration project validating the program’s genomic data in 98,622 participants. We sought to replicate known genetic associations for three diseases (atrial fibrillation [AF], coronary artery disease, type 2 diabetes [T2D]) and two quantitative traits (height and low-density lipoprotein [LDL]) by conducting common and rare variant analyses. We identified one known risk locus for AF, five loci for T2D, 143 loci for height, and nine loci for LDL. In gene-based burden tests for rare loss-of-function variants, we replicated associations between TTN and AF, GIGYF1 and T2D, ADAMTS17, ACAN, NPR2 and height, APOB, LDLR, PCSK9 and LDL. Our results are consistent with previous literature, indicating that the All of Us program is a reliable resource for advancing the understanding of complex diseases in diverse human populations.

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Fig. 1: Manhattan plots of genome-wide association studies.
Fig. 2: Associations between phenotypes and genes harboring rare variants.

Data availability

Access to individual-level data from the All of Us research program is available to researchers whose institution has signed a data use agreement with All of Us (https://www.researchallofus.org/register/). All of Us provides a publicly available data browser (https://databrowser.researchallofus.org/) containing aggregate-level participant data for users to explore the available data, including genomic variants. Electronic health records (EHR) data, used for phenotyping, belongs to the registered tier dataset. Whole-genome sequencing data belongs to the controlled tier dataset, which requires additional training to access.

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Acknowledgements

We would like to thank the All of Us research program participants, as this study and the database are possible because of their contributions. All of Us established core values and responsible strategies to sustain public trust in biomedical research. We hope the partnership between the participants and the program will benefit the participants and improve the health of future generations.

Funding

The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants. Dr. Ellinor is supported by grants from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 1R01HL157635), from the American Heart Association (18SFRN34110082), and from the European Union (MAESTRIA 965286). Dr. Lubitz previously received support from NIH grants R01HL139731 and R01HL157635, and American Heart Association 18SFRN34250007 during this project. Dr. Choi was previously supported by the NHLBI BioData Catalyst Fellows program.

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Author notes

  1. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    Xin Wang, Patrick T. Ellinor & Steven A. Lubitz

  2. Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Xin Wang, Justine Ryu, Patrick T. Ellinor, Steven A. Lubitz & Seung Hoan Choi

  3. Department of Biomedical Informatics, University of California San Diego Health System, La Jolla, CA, USA

    Jihoon Kim & Lucila Ohno-Machado

  4. All of Us Research Program, National Institutes of Health, Bethesda, MD, USA

    Andrea Ramirez

  5. Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA

    Kelsey R. Mayo

  6. Department of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Henry Condon

  7. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Nataraja Sarma Vaitinadin

  8. Section of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT, USA

    Lucila Ohno-Machado

  9. Graduate School of Public Health, San Diego State University, San Diego, CA, USA

    Greg A. Talavera

  10. Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA

    Patrick T. Ellinor & Steven A. Lubitz

  11. Department of Biostatistics, Boston University, Boston, MA, USA

    Seung Hoan Choi

Authors
  1. Xin Wang
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Consortia

All of Us Research Program

Contributions

XW and SHC conceptualized the study and analyzed the data. SHC, SAL, and PTE supervised this work. JR helped with analysis and manuscript editing. JK helped with phenotype definitions. AR and KRM are members of the All of Us research program and provided support for this work, including manuscript review. The All of Us Research Program provided all the data used in the current study. HC, NSV, LO, and GAT provided feedback for this project. XW, SHC, and SAL wrote the manuscript. All co-authors reviewed the manuscript.

Corresponding author

Correspondence to Seung Hoan Choi.

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Competing interests

The authors declare no competing non-financial interests but the following competing financial interests: PTE receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, and Pfizer; he has also served on advisory boards or consulted for Bayer AG and MyoKardia. SAL is a full-time employee of Novartis as of July 18, 2022. SAL has received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae.

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Wang, X., Ryu, J., Kim, J. et al. Common and rare variants associated with cardiometabolic traits across 98,622 whole-genome sequences in the All of Us research program. J Hum Genet 68, 565–570 (2023). https://doi.org/10.1038/s10038-023-01147-z

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