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Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study

Author

Listed:
  • Christopher DeBoever

    (Stanford University
    Stanford University)

  • Yosuke Tanigawa

    (Stanford University)

  • Malene E. Lindholm

    (Grail, Inc.)

  • Greg McInnes

    (Stanford University)

  • Adam Lavertu

    (Stanford University)

  • Erik Ingelsson

    (Stanford University School of Medicine)

  • Chris Chang

    (Grail, Inc.)

  • Euan A. Ashley

    (Stanford University)

  • Carlos D. Bustamante

    (Stanford University
    Stanford University)

  • Mark J. Daly

    (Analytical and Translational Genetics Unit
    Broad Institute of MIT and Harvard)

  • Manuel A. Rivas

    (Stanford University)

Abstract

Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as “human knockouts,” across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.

Suggested Citation

  • Christopher DeBoever & Yosuke Tanigawa & Malene E. Lindholm & Greg McInnes & Adam Lavertu & Erik Ingelsson & Chris Chang & Euan A. Ashley & Carlos D. Bustamante & Mark J. Daly & Manuel A. Rivas, 2018. "Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03910-9
    DOI: 10.1038/s41467-018-03910-9
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    Cited by:

    1. Keren Papier & Joshua R. Atkins & Tammy Y. N. Tong & Kezia Gaitskell & Trishna Desai & Chibuzor F. Ogamba & Mahboubeh Parsaeian & Gillian K. Reeves & Ian G. Mills & Tim J. Key & Karl Smith-Byrne & Rut, 2024. "Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Young Jin Kim & Sanghoon Moon & Mi Yeong Hwang & Sohee Han & Hye-Mi Jang & Jinhwa Kong & Dong Mun Shin & Kyungheon Yoon & Sung Min Kim & Jong-Eun Lee & Anubha Mahajan & Hyun-Young Park & Mark I. McCar, 2022. "The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Maik Pietzner & Eleanor Wheeler & Julia Carrasco-Zanini & Nicola D. Kerrison & Erin Oerton & Mine Koprulu & Jian’an Luan & Aroon D. Hingorani & Steve A. Williams & Nicholas J. Wareham & Claudia Langen, 2021. "Synergistic insights into human health from aptamer- and antibody-based proteomic profiling," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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