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Large-scale genome-wide enrichment analyses identify new trait-associated genes and pathways across 31 human phenotypes

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  • Xiang Zhu

    (Stanford University
    The University of Chicago)

  • Matthew Stephens

    (The University of Chicago
    The University of Chicago)

Abstract

Genome-wide association studies (GWAS) aim to identify genetic factors associated with phenotypes. Standard analyses test variants for associations individually. However, variant-level associations are hard to identify and can be difficult to interpret biologically. Enrichment analyses help address both problems by targeting sets of biologically related variants. Here we introduce a new model-based enrichment method that requires only GWAS summary statistics. Applying this method to interrogate 4,026 gene sets in 31 human phenotypes identifies many previously-unreported enrichments, including enrichments of endochondral ossification pathway for height, NFAT-dependent transcription pathway for rheumatoid arthritis, brain-related genes for coronary artery disease, and liver-related genes for Alzheimer’s disease. A key feature of our method is that inferred enrichments automatically help identify new trait-associated genes. For example, accounting for enrichment in lipid transport genes highlights association between MTTP and low-density lipoprotein levels, whereas conventional analyses of the same data found no significant variants near this gene.

Suggested Citation

  • Xiang Zhu & Matthew Stephens, 2018. "Large-scale genome-wide enrichment analyses identify new trait-associated genes and pathways across 31 human phenotypes," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06805-x
    DOI: 10.1038/s41467-018-06805-x
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    Cited by:

    1. Winn-Nuñez, Emily T. & Griffin, Maryclare & Crawford, Lorin, 2024. "A simple approach for local and global variable importance in nonlinear regression models," Computational Statistics & Data Analysis, Elsevier, vol. 194(C).

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