Human Genetics

, Volume 136, Issue 7, pp 911–919 | Cite as

Comprehensive evaluation of disease- and trait-specific enrichment for eight functional elements among GWAS-identified variants

  • Christina A. Markunas
  • Eric O. Johnson
  • Dana B. Hancock
Original Investigation


Genome-wide association study (GWAS)-identified variants are enriched for functional elements. However, we have limited knowledge of how functional enrichment may differ by disease/trait and tissue type. We tested a broad set of eight functional elements for enrichment among GWAS-identified SNPs (p < 5×10−8) from the NHGRI-EBI Catalog across seven disease/trait categories: cancer, cardiovascular disease, diabetes, autoimmune disease, psychiatric disease, neurological disease, and anthropometric traits. SNPs were annotated using HaploReg for the eight functional elements across any tissue: DNase sites, expression quantitative trait loci (eQTL), sequence conservation, enhancers, promoters, missense variants, sequence motifs, and protein binding sites. In addition, tissue-specific annotations were considered for brain vs. blood. Disease/trait SNPs were compared to a control set of 4809 SNPs matched to the GWAS SNPs (N = 1639) on allele frequency, gene density, distance to nearest gene, and linkage disequilibrium at ~3:1 ratio. Enrichment analyses were conducted using logistic regression, with Bonferroni correction. Overall, a significant enrichment was observed for all functional elements, except sequence motifs. Missense SNPs showed the strongest magnitude of enrichment. eQTLs were the only functional element significantly enriched across all diseases/traits. Magnitudes of enrichment were generally similar across diseases/traits, where enrichment was statistically significant. Blood vs. brain tissue effects on enrichment were dependent on disease/trait and functional element (e.g., cardiovascular disease: eQTLs P TissueDifference = 1.28 × 10−6 vs. enhancers P TissueDifference = 0.94). Identifying disease/trait-relevant functional elements and tissue types could provide new insight into the underlying biology, by guiding a priori GWAS analyses (e.g., brain enhancer elements for psychiatric disease) or facilitating post hoc interpretation.



This work was supported by Grants from NIDA [R01 DA035825 (PI: Hancock); R01 DA036583 (PI: Bierut, Co-Is: Johnson and Hancock)]. We would like to thank Drs. Nathan Gaddis and Yuelong Guo for their critical review of our manuscript.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 34 kb)
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Supplementary material 2 (DOCX 219 kb)
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Supplementary material 3 (DOCX 448 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Christina A. Markunas
    • 1
  • Eric O. Johnson
    • 1
    • 2
  • Dana B. Hancock
    • 1
  1. 1.Behavioral Health and Criminal Justice DivisionRTI InternationalResearch Triangle ParkUSA
  2. 2.Fellow ProgramRTI InternationalResearch Triangle ParkUSA

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