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Cited by 127Genomics and Rare DiseasesGenetic Associations and EpidemiologyCancer Genomics and Diagnostics

A deep catalogue of protein-coding variation in 983,578 individuals

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Sun, Kathie Y., Bai, Xiaodong, Chen, Siying, Bao, Suying, Zhang, Chuanyi, Kapoor, Manav, Backman, Joshua, Joseph, Tyler +349 more·2024·Nature
DOI 10.1038/s41586-024-07556-0PMC PMC11254753
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Abstract

Rare coding variants that substantially affect function provide insights into the biology of a gene 1–3. However, ascertaining the frequency of such variants requires large sample sizes 4–8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.

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Authors
Sun, K. Y., Bai, X., Chen, S., Bao, S., Zhang, C., Kapoor, M., Backman, J., Joseph, T., Maxwell, E., Mitra, G., Gorovits, A., Mansfield, A., Boutkov, B., Gokhale, S., Habegger, L., Marcketta, A., Locke, A. E., Ganel, L., Hawes, A., Kessler, M. D., Sharma, D., Staples, J., Bovijn, J., Gelfman, S., Di Gioia, A., Rajagopal, V. M., Lopez, A., Varela, J. R., Alegre-Díaz, J., Berumen, J., Tapia-Conyer, R., Kuri-Morales, P., Torres, J., Emberson, J., Collins, R., Regeneron Genetics Center, RGC Management and Leadership Team, Abecasis, G., Coppola, G., Deubler, A., Economides, A., Ferrando, A., Lotta, L. A., Shuldiner, A., Siminovitch, K., Operations, S. A. L., Beechert, C., Brian, E. D., Cremona, L. M., Du, H., Forsythe, C., Gu, Z., Guevara, K., Lattari, M., Manoochehri, K., Challa, P., Pradhan, M., Reynoso, R., Schiavo, R., Padilla, M. S., Wang, C., Wolf, S. E., Informatics, C., Averitt, A., Banerjee, N., Li, D., Malhotra, S., Mower, J., Sarwar, M., Staples, J. C., Yu, S., Zhang, A., Engineering, G. I. A. D., Bunyea, A., Punuru, K. P., Sreeram, S., Eom, G., Sultan, B., Lanche, R., Mahajan, V., Austin, E., O’Keeffe, S., Panea, R., Polanco, T., Rasool, A., Zhang, L., Edelstein, E., Guan, J., Krasheninina, O., Zarate, S., Mansfield, A. J., Maxwell, E. K., Sun, K., Science, A. G. A. D., Ferreira, M. A. R., Burch, K., Campos, A., Chen, L., Choi, S., Damask, A., Gaynor, S., Geraghty, B., Ghosh, A., Martinez, S. R., Gillies, C., Gurski, L., Herman, J., Jorgenson, E., Kessler, M., Kosmicki, J., Lin, N., Locke, A., Nakka, P., Landheer, K., Delaneau, O., Ghoussaini, M., Mbatchou, J., Moscati, A., Pandey, A., Pandit, A., Paulding, C., Ross, J., Sidore, C., Stahl, E., Suciu, M., VandeHaar, P., Vedantam, S., Vrieze, S., Zhang, J., Wang, R., Wu, K.-H., Ye, B., Zhang, B., Ziyatdinov, A., Zou, Y., Watanabe, K., Tang, M., Genetics, T. A., Hobbs, B., Silver, J., Palmer, W., Guerreiro, R., Joshi, A., Baldassari, A., Willer, C., Graham, S., Mayerhofer, E., Haas, M., Verweij, N., Hindy, G., De, T., Akbari, P., Sun, L., Sosina, O., Gilly, A., Dornbos, P., Rodriguez-Flores, J., Riaz, M., Tzoneva, G., Jallow, M. W., Alkelai, A., Ayer, A., Rajagopal, V., Kumar, V., Otto, J., Parikshak, N., Guvenek, A., Bras, J., Alvarez, S., Brown, J., He, J., Khiabanian, H., Revez, J., Skead, K., Zavala, V., Initiatives, R. P. M. A. S., Mitnaul, L. J., Jones, M. B., Chen, E., LeBlanc, M. G., Mighty, J., Nishtala, N., Rana, N., Rico-Varela, J., Hernandez, J., Operations, S. P. A. B., Fenney, A., Schwartz, R., Hankins, J., Hart, S., Coordinators, B. O. A. A., Perez-Beals, A., Solari, G., Rivera-Picart, J., Pagan, M., Siceron, S., Partners, R.-M. C., Cures, A., Gwynne, D., (ADAGES), A. D. A. G. E. S., III, Rotter, J. I., Weinreb, R., Amish, A.-R. M. D. I. T., Haines, J. L., Pericak-Vance, M. A., Stambolian, D., Albert Einstein College of Medicine, Barzilai, N., Suh, Y., Zhang, Z., Amish Connectome Project, Hong, E., Clinic, A. R., Mitchell, B., The Australia and New Zealand MS Genetics Consortium, Blackburn, N. B., Broadley, S., Fabis-Pedrini, M. J., Jokubaitis, V. G., Kermode, A. G., Kilpatrick, T. J., Lechner-Scott, J., Leslie, S., McComish, B. J., Motyer, A., Parnell, G. P., Scott, R. J., Taylor, B. V., Rubio, J. P., Center for Non-Communicable Diseases (CNCD), Saleheen, D., Hospital, C. C., Kaufman, K., Kottyan, L., Martin, L., Rothenberg, M. E., Columbia University, Ali, A., Raza, A., Study, D. H., Cohen, J., Diabetic Retinopathy Clinical Research (DRCR) Retina Network, Glassman, A., Duke University, Kraus, W. E., Newgard, C. B., Shah, S. H., Flinders University of South Australia, Craig, J., Hewitt, A., Biobank, I., Chalasani, N., Foroud, T., Liangpunsakul, S., Indiana University School of Medicine, Cox, N. J., Dolan, E., El-Charif, O., Travis, L. B., Wheeler, H., Gamazon, E., Permanente, K., Sakoda, L., Witte, J., Clinic, M., Lazaridis, K., (MCPS), M. C. P. S., Biobank, M.-D. G. H. S., Buchanan, A., Carey, D. J., Martin, C. L., Meyer, M. N., Retterer, K., Rolston, D., National Institute of Mental Health, Akula, N., Besançon, E., Detera-Wadleigh, S. D., Kassem, L., McMahon, F. J., Schulze, T. G., Northwestern University, Gordon, A., Smith, M., Varga, J., Biobank, P. M., Bradford, Y., Damrauer, S., DerOhannessian, S., Drivas, T., Dudek, S., Dunn, J., Haubein, N., Judy, R., Ko, Y.-A., Kripke, C. M., Livingstone, M., Naseer, N., Nerz, K. P., Poindexter, A., Risman, M., Santos, S., Sirugo, G., Stephanowski, J., Tran, T., Vadivieso, F., Verma, A., Verma, S. S., Weaver, J., Wollack, C., Rader, D. J., Ritchie, M., study, P. O.-A. A. A. G. G. (., O’Brien, J., Biobank, R. S. B., Bottinger, E., Cho, J., arthritis, U. G. I. A. A. W. R., Bridges, S. L., patients, U. W. E. S. O. S. L. E., Kimberly, R., University of California, L. A., Fejzo, M., University of Colorado School of Medicine, Spritz, R. A., University of Michigan Medical School, Elder, J. T., Nair, R. P., Stuart, P., Tsoi, L. C., University of Ottawa, Dent, R., McPherson, R., University of Pennsylvania, Keating, B., University of Pittsburgh, Kershaw, E. E., Papachristou, G., Whitcomb, D. C., University of Texas Health Science Center at Houston, Assassi, S., Mayes, M. D., Vanderbilt University Medical Center, Austin, E. D., Cantor, M., Thornton, T., Kang, H. M., Overton, J. D., Shuldiner, A. R., Cremona, M. L., Nafde, M., Baras, A., Abecasis, G., Marchini, J., Reid, J. G., Salerno, W., & Balasubramanian, S.
Affiliations
  • Regeneron (United States) (US)
  • Universidad Nacional Autónoma de México (MX)
  • University of Oxford (GB)
  • Northwestern University (US)
  • Flinders University (AU)
  • Albert Einstein College of Medicine (US)
  • Vanderbilt University Medical Center (US)
  • Case Western Reserve University (US)
  • University of Pittsburgh (US)
  • Center for Non-Communicable Diseases (PK)
  • Cincinnati Children's Hospital Medical Center (US)
  • Columbia University (US)
  • Duke University (US)
  • Indiana University School of Medicine (US)
  • National Institute of Mental Health (US)
  • University of California, Los Angeles (US)
  • University of Ottawa (CA)
  • University of Pennsylvania (US)
  • The University of Texas Health Science Center at Houston (US)
  • The Lundquist Institute (US)
Corresponding author
  • Salerno, William
  • Balasubramanian, Suganthi
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-05-20
Volume
631
Issue
8021
Pages
583-592
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-07556-0
PMC
PMC11254753
OpenAlex
W4398143407
Cited by
127
References
10
Citations by year
2026: 56 · 2025: 58 · 2024: 12 · 2023: 1
FWCI
30.96
Type
journal article
Language
en
Update notices
correction (2025-01-08)
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs
  • Kaiser Permanente
  • University of Pennsylvania
  • Northwestern University
  • Cincinnati Children's Hospital Medical Center
  • University of Texas Southwestern Medical Center
  • University of Pittsburgh
  • University of Ottawa
  • Regeneron Pharmaceuticals
  • University of Texas Health Science Center at Houston
  • Vanderbilt University Medical Center
  • University of Tasmania
  • Monash University
  • Flinders University
  • Griffith University
  • Murdoch University
  • Menzies Institute for Medical Research
  • National Institutes of Health
  • University of California, Los Angeles
  • Medical School, University of Michigan
  • School of Medicine, Indiana University
  • Medical Research Council (MC_UU_00017/2, MR/Z504543/1)
  • National Institute of Mental Health (ZIAMH002843)
  • National Cancer Institute (CA157823, R01CA201358, R01CA157823)
  • University of Colorado School of Medicine, Anschutz Medical Campus
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
human genetic variation, loss-of-function mutations, missense mutations, cryptic splice site, variant interpretation, precision medicine, exome sequencing

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