Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Nat Commun. 2021 Nov 16;12(1):6618. doi: 10.1038/s41467-021-26783-x.


Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Publication types

  • Meta-Analysis

MeSH terms

  • Cytokine Receptor Common beta Subunit
  • Dual Specificity Phosphatase 1 / chemistry
  • Dual Specificity Phosphatase 1 / genetics*
  • Dual Specificity Phosphatase 1 / metabolism
  • Eczema / diagnosis*
  • Eczema / genetics*
  • Gene Expression
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Matrix Attachment Region Binding Proteins
  • Polymorphism, Single Nucleotide
  • Rare Diseases / genetics
  • Receptor, Notch4 / chemistry
  • Receptor, Notch4 / genetics*
  • Receptor, Notch4 / metabolism
  • Sodium-Hydrogen Exchangers / chemistry
  • Sodium-Hydrogen Exchangers / genetics*
  • Sodium-Hydrogen Exchangers / metabolism


  • CSF2RB protein, human
  • Cytokine Receptor Common beta Subunit
  • Matrix Attachment Region Binding Proteins
  • NOTCH4 protein, human
  • Receptor, Notch4
  • SATB1 protein, human
  • SLC9A4 protein, human
  • Sodium-Hydrogen Exchangers
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1