Identification of OCA2 as a novel locus for the co-morbidity of asthma-plus-eczema

Clin Exp Allergy. 2022 Jan;52(1):70-81. doi: 10.1111/cea.13972. Epub 2021 Jul 3.


Background: Numerous genes have been associated with the three most common allergic diseases (asthma, allergic rhinitis or eczema) but these genes explain only a part of the heritability. In the vast majority of genetic studies, complex phenotypes such as co-morbidity of two of these diseases, have not been considered. This may partly explain missing heritability.

Objective: To identify genetic variants specifically associated with the co-morbidity of asthma-plus-eczema.

Methods: We first conducted a meta-analysis of four GWAS (Genome-Wide Association Study) of the combined asthma-plus-eczema phenotype (total of 8807 European-ancestry subjects of whom 1208 subjects had both asthma and eczema). To assess whether the association with SNP(s) was specific to the co-morbidity, we also conducted a meta-analysis of homogeneity test of association according to disease status ("asthma-plus-eczema" vs. the presence of only one disease "asthma only or eczema only"). We then used a joint test by combining the two test statistics from the co-morbidity-SNP association and the phenotypic heterogeneity of SNP effect meta-analyses.

Results: Seven SNPs were detected for specific association to the asthma-plus-eczema co-morbidity, two with significant and five with suggestive evidence using the joint test after correction for multiple testing. The two significant SNPs are located in the OCA2 gene (Oculocutaneous Albinism II), a new locus never detected for significant evidence of association with any allergic disease. This gene is a promising candidate gene, because of its link to skin and lung diseases, and to epithelial barrier and immune mechanisms.

Conclusion: Our study underlines the importance of studying sub-phenotypes as co-morbidities to detect new susceptibility genes.

Keywords: ALSPAC; EGEA; GABRIELA; GWAS; SLSJ; asthma; co-morbidity; eczema; phenotypic heterogeneity.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albinism, Oculocutaneous*
  • Asthma* / epidemiology
  • Asthma* / genetics
  • Comorbidity
  • Eczema* / epidemiology
  • Eczema* / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Membrane Transport Proteins / genetics
  • Morbidity
  • Rhinitis, Allergic* / epidemiology
  • Rhinitis, Allergic* / genetics


  • Membrane Transport Proteins
  • OCA2 protein, human

Supplementary concepts

  • Oculocutaneous albinism type 2