Comprehensive Analysis of Tissue-wide Gene Expression and Phenotype Data Reveals Tissues Affected in Rare Genetic Disorders

Ariel Feiglin, Bryce K. Allen, Isaac S. Kohane, Sek Won Kong

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Linking putatively pathogenic variants to the tissues they affect is necessary for determining the correct diagnostic workup and therapeutic regime in undiagnosed patients. Here, we explored how gene expression across healthy tissues can be used to infer this link. We integrated 6,665 tissue-wide transcriptomes with genetic disorder knowledge bases covering 3,397 diseases. Receiver-operating characteristics (ROC) analysis using expression levels in each tissue and across tissues indicated significant but modest associations between elevated expression and phenotype for most tissues (maximum area under ROC curve = 0.69). At extreme elevation, associations were marked. Upregulation of disease genes in affected tissues was pronounced for genes associated with autosomal dominant over recessive disorders. Pathways enriched for genes expressed and associated with phenotypes highlighted tissue functionality, including lipid metabolism in spleen and DNA repair in adipose tissue. These results suggest features useful for evaluating the likelihood of particular tissue manifestations in genetic disorders. The web address of an interactive platform integrating these data is provided.

Original languageEnglish
Pages (from-to)140-148.e2
JournalCell Systems
Volume5
Issue number2
DOIs
StatePublished - 23 Aug 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017

Funding

We thank Susanne Churchill, Inbar Fried, and Daria Prilutsky for their comments on the manuscript. We thank all the people involved in creating and maintaining high-quality resources such as OMIM, HPO, and GTEx. This work was funded by the National Institute of Mental Health (5P50MH106933-03) and the National Human Genome Research Institute (5U01HG007530-03). SW.K. was supported by NIH R01MH107205 and P50MH094267. We thank Susanne Churchill, Inbar Fried, and Daria Prilutsky for their comments on the manuscript. We thank all the people involved in creating and maintaining high-quality resources such as OMIM, HPO, and GTEx. This work was funded by the National Institute of Mental Health ( 5P50MH106933-03 ) and the National Human Genome Research Institute ( 5U01HG007530-03 ). SW.K. was supported by NIH R01MH107205 and P50MH094267 .

FundersFunder number
GTEx
NIH R01MH107205
National Institutes of Health
National Institute of Mental Health5P50MH106933-03, R01MH107205, P50MH094267
National Human Genome Research InstituteU01HG007530

    Keywords

    • GTEx
    • HPO
    • OMIM
    • genetic disorders
    • human phenotype ontology
    • tissue-specific disease manifestation

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