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Multi-context genetic modeling of transcriptional regulation resolves novel disease loci

Author

Listed:
  • Mike Thompson

    (University of California Los Angeles)

  • Mary Grace Gordon

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Andrew Lu

    (University of California Los Angeles)

  • Anchit Tandon

    (Indian Institute of Technology Delhi)

  • Eran Halperin

    (University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles)

  • Alexander Gusev

    (Dana-Farber Cancer Institute and Harvard Medical School
    Brigham and Women’s Hospital)

  • Chun Jimmie Ye

    (University of California, San Francisco
    University of California, San Francisco
    Chan-Zuckerberg Biohub
    University of California, San Francisco)

  • Brunilda Balliu

    (University of California Los Angeles)

  • Noah Zaitlen

    (University of California Los Angeles
    University of California Los Angeles)

Abstract

A majority of the variants identified in genome-wide association studies fall in non-coding regions of the genome, indicating their mechanism of impact is mediated via gene expression. Leveraging this hypothesis, transcriptome-wide association studies (TWAS) have assisted in both the interpretation and discovery of additional genes associated with complex traits. However, existing methods for conducting TWAS do not take full advantage of the intra-individual correlation inherently present in multi-context expression studies and do not properly adjust for multiple testing across contexts. We introduce CONTENT—a computationally efficient method with proper cross-context false discovery correction that leverages correlation structure across contexts to improve power and generate context-specific and context-shared components of expression. We apply CONTENT to bulk multi-tissue and single-cell RNA-seq data sets and show that CONTENT leads to a 42% (bulk) and 110% (single cell) increase in the number of genetically predicted genes relative to previous approaches. We find the context-specific component of expression comprises 30% of heritability in tissue-level bulk data and 75% in single-cell data, consistent with cell-type heterogeneity in bulk tissue. In the context of TWAS, CONTENT increases the number of locus-phenotype associations discovered by over 51% relative to previous methods across 22 complex traits.

Suggested Citation

  • Mike Thompson & Mary Grace Gordon & Andrew Lu & Anchit Tandon & Eran Halperin & Alexander Gusev & Chun Jimmie Ye & Brunilda Balliu & Noah Zaitlen, 2022. "Multi-context genetic modeling of transcriptional regulation resolves novel disease loci," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33212-0
    DOI: 10.1038/s41467-022-33212-0
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    1. Cristina M. Lanata & Ishan Paranjpe & Joanne Nititham & Kimberly E. Taylor & Milena Gianfrancesco & Manish Paranjpe & Shan Andrews & Sharon A. Chung & Brooke Rhead & Lisa F. Barcellos & Laura Trupin &, 2019. "A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Noam D. Beckmann & Wei-Jye Lin & Minghui Wang & Ariella T. Cohain & Alexander W. Charney & Pei Wang & Weiping Ma & Ying-Chih Wang & Cheng Jiang & Mickael Audrain & Phillip H. Comella & Amanda K. Fakir, 2020. "Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    3. Tanya M. Teslovich & Kiran Musunuru & Albert V. Smith & Andrew C. Edmondson & Ioannis M. Stylianou & Masahiro Koseki & James P. Pirruccello & Samuli Ripatti & Daniel I. Chasman & Cristen J. Willer & C, 2010. "Biological, clinical and population relevance of 95 loci for blood lipids," Nature, Nature, vol. 466(7307), pages 707-713, August.
    4. Timothée Flutre & Xiaoquan Wen & Jonathan Pritchard & Matthew Stephens, 2013. "A Statistical Framework for Joint eQTL Analysis in Multiple Tissues," PLOS Genetics, Public Library of Science, vol. 9(5), pages 1-13, May.
    5. Heather E Wheeler & Kaanan P Shah & Jonathon Brenner & Tzintzuni Garcia & Keston Aquino-Michaels & GTEx Consortium & Nancy J Cox & Dan L Nicolae & Hae Kyung Im, 2016. "Survey of the Heritability and Sparse Architecture of Gene Expression Traits across Human Tissues," PLOS Genetics, Public Library of Science, vol. 12(11), pages 1-23, November.
    6. Kiran Musunuru & Alanna Strong & Maria Frank-Kamenetsky & Noemi E. Lee & Tim Ahfeldt & Katherine V. Sachs & Xiaoyu Li & Hui Li & Nicolas Kuperwasser & Vera M. Ruda & James P. Pirruccello & Brian Muchm, 2010. "From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus," Nature, Nature, vol. 466(7307), pages 714-719, August.
    7. Yiguo Shen & David Kapfhamer & Angela M. Minnella & Ji-Eun Kim & Seok Joon Won & Yanting Chen & Yong Huang & Ley Hian Low & Stephen M. Massa & Raymond A. Swanson, 2017. "Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    8. Alvaro N Barbeira & Milton Pividori & Jiamao Zheng & Heather E Wheeler & Dan L Nicolae & Hae Kyung Im, 2019. "Integrating predicted transcriptome from multiple tissues improves association detection," PLOS Genetics, Public Library of Science, vol. 15(1), pages 1-20, January.
    9. Yukinori Okada & Di Wu & Gosia Trynka & Towfique Raj & Chikashi Terao & Katsunori Ikari & Yuta Kochi & Koichiro Ohmura & Akari Suzuki & Shinji Yoshida & Robert R. Graham & Arun Manoharan & Ward Ortman, 2014. "Genetics of rheumatoid arthritis contributes to biology and drug discovery," Nature, Nature, vol. 506(7488), pages 376-381, February.
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