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Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms

Author

Listed:
  • Milton Pividori

    (University of Pennsylvania
    University of Colorado School of Medicine)

  • Sumei Lu

    (Children’s Hospital of Philadelphia)

  • Binglan Li

    (Stanford University)

  • Chun Su

    (Children’s Hospital of Philadelphia)

  • Matthew E. Johnson

    (Children’s Hospital of Philadelphia)

  • Wei-Qi Wei

    (Vanderbilt University Medical Center)

  • Qiping Feng

    (Vanderbilt University Medical Center)

  • Bahram Namjou

    (Cincinnati Children’s Hospital Medical Center)

  • Krzysztof Kiryluk

    (Columbia University)

  • Iftikhar J. Kullo

    (Mayo Clinic)

  • Yuan Luo

    (Northwestern University)

  • Blair D. Sullivan

    (Kahlert School of Computing, University of Utah)

  • Benjamin F. Voight

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Carsten Skarke

    (University of Pennsylvania)

  • Marylyn D. Ritchie

    (University of Pennsylvania)

  • Struan F. A. Grant

    (University of Pennsylvania
    Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • Casey S. Greene

    (University of Colorado School of Medicine
    University of Colorado School of Medicine)

Abstract

Genes act in concert with each other in specific contexts to perform their functions. Determining how these genes influence complex traits requires a mechanistic understanding of expression regulation across different conditions. It has been shown that this insight is critical for developing new therapies. Transcriptome-wide association studies have helped uncover the role of individual genes in disease-relevant mechanisms. However, modern models of the architecture of complex traits predict that gene-gene interactions play a crucial role in disease origin and progression. Here we introduce PhenoPLIER, a computational approach that maps gene-trait associations and pharmacological perturbation data into a common latent representation for a joint analysis. This representation is based on modules of genes with similar expression patterns across the same conditions. We observe that diseases are significantly associated with gene modules expressed in relevant cell types, and our approach is accurate in predicting known drug-disease pairs and inferring mechanisms of action. Furthermore, using a CRISPR screen to analyze lipid regulation, we find that functionally important players lack associations but are prioritized in trait-associated modules by PhenoPLIER. By incorporating groups of co-expressed genes, PhenoPLIER can contextualize genetic associations and reveal potential targets missed by single-gene strategies.

Suggested Citation

  • Milton Pividori & Sumei Lu & Binglan Li & Chun Su & Matthew E. Johnson & Wei-Qi Wei & Qiping Feng & Bahram Namjou & Krzysztof Kiryluk & Iftikhar J. Kullo & Yuan Luo & Blair D. Sullivan & Benjamin F. V, 2023. "Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41057-4
    DOI: 10.1038/s41467-023-41057-4
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    References listed on IDEAS

    as
    1. Alexander Lachmann & Denis Torre & Alexandra B. Keenan & Kathleen M. Jagodnik & Hoyjin J. Lee & Lily Wang & Moshe C. Silverstein & Avi Ma’ayan, 2018. "Massive mining of publicly available RNA-seq data from human and mouse," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    3. Mark B. Gerstein & Anshul Kundaje & Manoj Hariharan & Stephen G. Landt & Koon-Kiu Yan & Chao Cheng & Xinmeng Jasmine Mu & Ekta Khurana & Joel Rozowsky & Roger Alexander & Renqiang Min & Pedro Alves & , 2012. "Architecture of the human regulatory network derived from ENCODE data," Nature, Nature, vol. 489(7414), pages 91-100, September.
    4. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    5. Christiaan A. Leeuw & Sven Stringer & Ilona A. Dekkers & Tom Heskes & Danielle Posthuma, 2018. "Conditional and interaction gene-set analysis reveals novel functional pathways for blood pressure," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    6. Wouter Meuleman & Alexander Muratov & Eric Rynes & Jessica Halow & Kristen Lee & Daniel Bates & Morgan Diegel & Douglas Dunn & Fidencio Neri & Athanasios Teodosiadis & Alex Reynolds & Eric Haugen & Je, 2020. "Index and biological spectrum of human DNase I hypersensitive sites," Nature, Nature, vol. 584(7820), pages 244-251, August.
    7. Lawrence Hubert & Phipps Arabie, 1985. "Comparing partitions," Journal of Classification, Springer;The Classification Society, vol. 2(1), pages 193-218, December.
    8. Anshul Kundaje & Wouter Meuleman & Jason Ernst & Misha Bilenky & Angela Yen & Alireza Heravi-Moussavi & Pouya Kheradpour & Zhizhuo Zhang & Jianrong Wang & Michael J. Ziller & Viren Amin & John W. Whit, 2015. "Integrative analysis of 111 reference human epigenomes," Nature, Nature, vol. 518(7539), pages 317-330, February.
    9. Tune H. Pers & Juha M. Karjalainen & Yingleong Chan & Harm-Jan Westra & Andrew R. Wood & Jian Yang & Julian C. Lui & Sailaja Vedantam & Stefan Gustafsson & Tonu Esko & Tim Frayling & Elizabeth K. Spel, 2015. "Biological interpretation of genome-wide association studies using predicted gene functions," Nature Communications, Nature, vol. 6(1), pages 1-9, May.
    10. Carles A. Boix & Benjamin T. James & Yongjin P. Park & Wouter Meuleman & Manolis Kellis, 2021. "Regulatory genomic circuitry of human disease loci by integrative epigenomics," Nature, Nature, vol. 590(7845), pages 300-307, February.
    11. Robin Andersson & Claudia Gebhard & Irene Miguel-Escalada & Ilka Hoof & Jette Bornholdt & Mette Boyd & Yun Chen & Xiaobei Zhao & Christian Schmidl & Takahiro Suzuki & Evgenia Ntini & Erik Arner & Eivi, 2014. "An atlas of active enhancers across human cell types and tissues," Nature, Nature, vol. 507(7493), pages 455-461, March.
    12. 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.
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