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Cited by 284Genetic Associations and EpidemiologyGenomics and Rare DiseasesBioinformatics and Genomic Networks

Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes

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Karczewski, Konrad J., Solomonson, Matthew, Chao, Katherine R., Goodrich, Julia K., Tiao, Grace, Lu, Wenhan, Riley-Gillis, Bridget M., Tsai, Ellen A. +37 more·2022·Cell Genomics
DOI 10.1016/j.xgen.2022.100168PMC PMC9903662

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Abstract

Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been explored at scale. Exome-sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variations across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 394,841 individuals in the UK Biobank with exome-sequence data. We find that the discovery of genetic associations is tightly linked to frequency and is correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare-variant association results.

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Crossref · 10.1016/j.xgen.2022.100168

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  • Deleterious missense variation in REPS1 is nominally associated with lower LDL-C (β = -0.00175, P = 0.00173).

    “and lower LDL-C ( β = -0.00175, P = 0.00173) (Table 1).”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [24]

    The Results section discusses missense-variant associations generally and reports an LDL-cholesterol association for PCSK9, not REPS1 (page unavailable). Searches for REPS1 and the stated β and P values found no passage in our copy that verifies the claimed REPS1 association. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Deleterious missense variation in REPS1 is nominally associated with lower total cholesterol (β = -0.00164, P = 0.00277).

    “lower total cholesterol ( β = -0.00164, P = 0.00277)”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [24]

    The Results section (‘Biological insights from rare-variant association results’; page unavailable) says the authors released their full association dataset, but the passage lists other genes and does not report a REPS1–total-cholesterol result. Searches for REPS1 and the stated β and P values found no matching passage in our copy, so the specific association cannot be verified from it. (LLM, conf=0.70)

    Experimental — accuracy not yet measured

  • Deleterious missense variation in REPS1 is nominally associated with lower APOB (β = -0.00163, P = 0.00344).

    “we found that deleterious missense variation in REPS1 was nominally associated with lower APOB ( β = -0.00163, P = 0.00344)”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [24]

    The Results section on rare-variant associations discusses deleterious missense variants in general, but does not report a REPS1–APOB association. Searches of our copy for REPS1, APOB and P = 0.00344 found no passage verifying the stated effect size or P value; page numbers were not available. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • pLoF variants in CTSA were associated with lower total cholesterol (β = -0.00270, P = 0.0176).

    “and lower total cholesterol ( β = -0.00270, P = 0.0176)”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [24]

    The Results section, “Biological insights from rare-variant association results” (page unavailable), reports a pLoF association between PCSK9 and LDL cholesterol, not CTSA and total cholesterol. Searches for CTSA, total cholesterol, β = -0.00270, and P = 0.0176 found no passage in our copy reporting the claimed association or statistics. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • pLoF variants in CTSA from UK Biobank exomes were associated with lower APOB (β = -0.00255, P = 0.0276).

    “Analysis of protein-coding variation in CTSA from UK Biobank exomes revealed that pLoF variants were associated with lower APOB ( β = -0.00255, P = 0.0276)”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [24]

    The Results section describes UK Biobank exome association testing and gives examples involving other genes, but does not report a CTSA–APOB association. Searches for CTSA, APOB, β = -0.00255, and P = 0.0276 found no passage establishing the claimed direction or statistics in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Authors
Karczewski, K. J., Solomonson, M., Chao, K. R., Goodrich, J. K., Tiao, G., Lu, W., Riley-Gillis, B. M., Tsai, E. A., Kim, H. I., Zheng, X., Rahimov, F., Esmaeeli, S., Grundstad, A. J., Reppell, M., Waring, J., Jacob, H., Sexton, D., Bronson, P. G., Chen, X., Hu, X., Goldstein, J. I., King, D., Vittal, C., Poterba, T., Palmer, D. S., Churchhouse, C., Howrigan, D. P., Zhou, W., Watts, N. A., Nguyen, K., Nguyen, H., Mason, C., Farnham, C., Tolonen, C., Gauthier, L. D., Gupta, N., MacArthur, D. G., Rehm, H. L., Seed, C., Philippakis, A. A., Daly, M. J., Davis, J. W., Runz, H., Miller, M. R., & Neale, B. M.
Affiliations
  • Broad Institute (US)
  • AbbVie (United States) (US)
  • Biogen (United States) (US)
  • Pfizer (United States) (US)
Corresponding author
Karczewski, Konrad J.
ORCID
Venue
Cell Genomics
Publisher
Elsevier BV
Published
2022-09
Volume
2
Issue
9
Pages
100168
ISSN
2666-979X (ISSN-L)
DOI
10.1016/j.xgen.2022.100168
PMC
PMC9903662
OpenAlex
W4291582462
Cited by
284
References
7
Citations by year
2026: 65 · 2025: 78 · 2024: 59 · 2023: 56 · 2022: 26
FWCI
33.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Genomics (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075787)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
Keywords
rare coding variants, gene-based association, phenotypes, variant frequency, natural selection

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