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Polygenic architecture of rare coding variation across 394,783 exomes

Author

Listed:
  • Daniel J. Weiner

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Ajay Nadig

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Karthik A. Jagadeesh

    (Broad Institute of MIT and Harvard
    Harvard T.H. Chan School of Public Health)

  • Kushal K. Dey

    (Broad Institute of MIT and Harvard
    Harvard T.H. Chan School of Public Health)

  • Benjamin M. Neale

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Elise B. Robinson

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Konrad J. Karczewski

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Luke J. O’Connor

    (Broad Institute of MIT and Harvard)

Abstract

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1–3. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear4. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes5. Rare coding variants (allele frequency

Suggested Citation

  • Daniel J. Weiner & Ajay Nadig & Karthik A. Jagadeesh & Kushal K. Dey & Benjamin M. Neale & Elise B. Robinson & Konrad J. Karczewski & Luke J. O’Connor, 2023. "Polygenic architecture of rare coding variation across 394,783 exomes," Nature, Nature, vol. 614(7948), pages 492-499, February.
    • Handle: RePEc:nat:nature:v:614:y:2023:i:7948:d:10.1038_s41586-022-05684-z
    DOI: 10.1038/s41586-022-05684-z
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    Cited by:

    1. Rebecca Keener & Surya B. Chhetri & Carla J. Connelly & Margaret A. Taub & Matthew P. Conomos & Joshua Weinstock & Bohan Ni & Benjamin Strober & Stella Aslibekyan & Paul L. Auer & Lucas Barwick & Lewi, 2024. "Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Xiao-Yu He & Bang-Sheng Wu & Liu Yang & Yu Guo & Yue-Ting Deng & Ze-Yu Li & Chen-Jie Fei & Wei-Shi Liu & Yi-Jun Ge & Jujiao Kang & Jianfeng Feng & Wei Cheng & Qiang Dong & Jin-Tai Yu, 2024. "Genetic associations of protein-coding variants in venous thromboembolism," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Ozvan Bocher & Cristen J. Willer & Eleftheria Zeggini, 2023. "Unravelling the genetic architecture of human complex traits through whole genome sequencing," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    5. Matthew Tegtmeyer & Jatin Arora & Samira Asgari & Beth A. Cimini & Ajay Nadig & Emily Peirent & Dhara Liyanage & Gregory P. Way & Erin Weisbart & Aparna Nathan & Tiffany Amariuta & Kevin Eggan & Marzi, 2024. "High-dimensional phenotyping to define the genetic basis of cellular morphology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Ghislain Rocheleau & Shoa L. Clarke & Gaëlle Auguste & Natalie R. Hasbani & Alanna C. Morrison & Adam S. Heath & Lawrence F. Bielak & Kruthika R. Iyer & Erica P. Young & Nathan O. Stitziel & Goo Jun &, 2024. "Rare variant contribution to the heritability of coronary artery disease," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Liu Yang & Ya-Nan Ou & Bang-Sheng Wu & Wei-Shi Liu & Yue-Ting Deng & Xiao-Yu He & Yi-Lin Chen & Jujiao Kang & Chen-Jie Fei & Ying Zhu & Lan Tan & Qiang Dong & Jianfeng Feng & Wei Cheng & Jin-Tai Yu, 2024. "Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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