IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-54678-0.html
   My bibliography  Save this article

A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank

Author

Listed:
  • Celine A. Manigbas

    (Icahn School of Medicine at Mount)

  • Bharati Jadhav

    (Icahn School of Medicine at Mount)

  • Paras Garg

    (Icahn School of Medicine at Mount)

  • Mariya Shadrina

    (Icahn School of Medicine at Mount)

  • William Lee

    (Icahn School of Medicine at Mount)

  • Gabrielle Altman

    (Icahn School of Medicine at Mount)

  • Alejandro Martin-Trujillo

    (Icahn School of Medicine at Mount)

  • Andrew J. Sharp

    (Icahn School of Medicine at Mount)

Abstract

Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing fine-mapped associations with 73 traits. We replicate 23 of 31 (74%) of these associations in the All of Us cohort. While this set includes several known repeat expansion disorders, novel associations we found are attributable to common polymorphic variation in TR length rather than rare expansions and include e.g. a coding polyhistidine motif in HRCT1 influencing risk of hypertension and a poly(CGC) in the 5’UTR of GNB2 influencing heart rate. Fine-mapped TRs are strongly enriched for associations with local gene expression and DNA methylation. Our study highlights the contribution of multi-allelic TRs to the “missing heritability” of the human genome.

Suggested Citation

  • Celine A. Manigbas & Bharati Jadhav & Paras Garg & Mariya Shadrina & William Lee & Gabrielle Altman & Alejandro Martin-Trujillo & Andrew J. Sharp, 2024. "A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54678-0
    DOI: 10.1038/s41467-024-54678-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-54678-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-54678-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Teri A. Manolio & Francis S. Collins & Nancy J. Cox & David B. Goldstein & Lucia A. Hindorff & David J. Hunter & Mark I. McCarthy & Erin M. Ramos & Lon R. Cardon & Aravinda Chakravarti & Judy H. Cho &, 2009. "Finding the missing heritability of complex diseases," Nature, Nature, vol. 461(7265), pages 747-753, October.
    2. Wen-Wei Liao & Mobin Asri & Jana Ebler & Daniel Doerr & Marina Haukness & Glenn Hickey & Shuangjia Lu & Julian K. Lucas & Jean Monlong & Haley J. Abel & Silvia Buonaiuto & Xian H. Chang & Haoyu Cheng , 2023. "A draft human pangenome reference," Nature, Nature, vol. 617(7960), pages 312-324, May.
    3. Oliver Stegle & Leopold Parts & Richard Durbin & John Winn, 2010. "A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-11, May.
    4. Shubham Saini & Ileena Mitra & Nima Mousavi & Stephanie Feupe Fotsing & Melissa Gymrek, 2018. "A reference haplotype panel for genome-wide imputation of short tandem repeats," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sean A. Misek & Aaron Fultineer & Jeremie Kalfon & Javad Noorbakhsh & Isabella Boyle & Priyanka Roy & Joshua Dempster & Lia Petronio & Katherine Huang & Alham Saadat & Thomas Green & Adam Brown & John, 2024. "Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Ilias Georgakopoulos-Soares & Chengyu Deng & Vikram Agarwal & Candace S. Y. Chan & Jingjing Zhao & Fumitaka Inoue & Nadav Ahituv, 2023. "Transcription factor binding site orientation and order are major drivers of gene regulatory activity," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Lin Yuan & Chang-An Yuan & De-Shuang Huang, 2017. "FAACOSE: A Fast Adaptive Ant Colony Optimization Algorithm for Detecting SNP Epistasis," Complexity, Hindawi, vol. 2017, pages 1-10, September.
    4. Chang Lu & Jan Zaucha & Rihab Gam & Hai Fang & Smithers & Matt E. Oates & Miguel Bernabe-Rubio & James Williams & Natalie Zelenka & Arun Prasad Pandurangan & Himani Tandon & Hashem Shihab & Raju Kalai, 2023. "Hypothesis-free phenotype prediction within a genetics-first framework," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Seong Kyu Han & Michelle T. McNulty & Christopher J. Benway & Pei Wen & Anya Greenberg & Ana C. Onuchic-Whitford & Dongkeun Jang & Jason Flannick & Noël P. Burtt & Parker C. Wilson & Benjamin D. Humph, 2023. "Mapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Ian Barnett & Rajarshi Mukherjee & Xihong Lin, 2017. "The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 112(517), pages 64-76, January.
    7. Bingxin Zhao & Fei Zou, 2022. "On polygenic risk scores for complex traits prediction," Biometrics, The International Biometric Society, vol. 78(2), pages 499-511, June.
    8. von Stumm, Sophie & Kandaswamy, Radhika & Maxwell, Jessye, 2023. "Gene-environment interplay in early life cognitive development," Intelligence, Elsevier, vol. 98(C).
    9. Satria P. Sajuthi & Jamie L. Everman & Nathan D. Jackson & Benjamin Saef & Cydney L. Rios & Camille M. Moore & Angel C. Y. Mak & Celeste Eng & Ana Fairbanks-Mahnke & Sandra Salazar & Jennifer Elhawary, 2022. "Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Barbara E Stranger & Stephen B Montgomery & Antigone S Dimas & Leopold Parts & Oliver Stegle & Catherine E Ingle & Magda Sekowska & George Davey Smith & David Evans & Maria Gutierrez-Arcelus & Alkes P, 2012. "Patterns of Cis Regulatory Variation in Diverse Human Populations," PLOS Genetics, Public Library of Science, vol. 8(4), pages 1-13, April.
    11. Yu Yan & Hongbo Liu & Amin Abedini & Xin Sheng & Matthew Palmer & Hongzhe Li & Katalin Susztak, 2024. "Unraveling the epigenetic code: human kidney DNA methylation and chromatin dynamics in renal disease development," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Margaret Sunitha Selvaraj & Xihao Li & Zilin Li & Akhil Pampana & David Y. Zhang & Joseph Park & Stella Aslibekyan & Joshua C. Bis & Jennifer A. Brody & Brian E. Cade & Lee-Ming Chuang & Ren-Hua Chung, 2022. "Whole genome sequence analysis of blood lipid levels in >66,000 individuals," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    13. Bar Haim Y. & Booth James G. & Wells Martin T., 2012. "A Mixture-Model Approach for Parallel Testing for Unequal Variances," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(1), pages 1-21, January.
    14. Nicoló Fusi & Oliver Stegle & Neil D Lawrence, 2012. "Joint Modelling of Confounding Factors and Prominent Genetic Regulators Provides Increased Accuracy in Genetical Genomics Studies," PLOS Computational Biology, Public Library of Science, vol. 8(1), pages 1-9, January.
    15. Jin Hyun Ju & Sushila A Shenoy & Ronald G Crystal & Jason G Mezey, 2017. "An independent component analysis confounding factor correction framework for identifying broad impact expression quantitative trait loci," PLOS Computational Biology, Public Library of Science, vol. 13(5), pages 1-26, May.
    16. Jennifer A. Smith & Wei Zhao & Kalyn Yasutake & Carmella August & Scott M. Ratliff & Jessica D. Faul & Eric Boerwinkle & Aravinda Chakravarti & Ana V. Diez Roux & Yan Gao & Michael E. Griswold & Gerar, 2017. "Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies," IJERPH, MDPI, vol. 14(12), pages 1-18, December.
    17. Caitlin Guccione & Lucas Patel & Yoshihiko Tomofuji & Daniel McDonald & Antonio Gonzalez & Gregory D. Sepich-Poore & Kyuto Sonehara & Mohsen Zakeri & Yang Chen & Amanda Hazel Dilmore & Neil Damle & Se, 2025. "Incomplete human reference genomes can drive false sex biases and expose patient-identifying information in metagenomic data," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    18. Cristian Groza & Xun Chen & Travis J. Wheeler & Guillaume Bourque & Clément Goubert, 2024. "A unified framework to analyze transposable element insertion polymorphisms using graph genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Remo Monti & Pia Rautenstrauch & Mahsa Ghanbari & Alva Rani James & Matthias Kirchler & Uwe Ohler & Stefan Konigorski & Christoph Lippert, 2022. "Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    20. M. A. Zouache & B. T. Richards & C. M. Pappas & R. A. Anstadt & J. Liu & T. Corsetti & S. Matthews & N. A. Seager & S. Schmitz-Valckenberg & M. Fleckenstein & W. C. Hubbard & J. Thomas & J. L. Hageman, 2024. "Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54678-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.