A multi-ethnic genome-wide association study of 21 000 cases and 95 000 controls identifies 11 novel genetic variants associated with atopic dermatitis
Paternoster L, Standl M, Baurecht H, Waage J, Hotze M, Curtin JA, Bonnelykke K, Glass D, Tian C, Melen E, Sleiman P, Feenstra B, Pino-Yanes M, den Dekker HT, Bustamante M, Marenholz I, Jacobsson B, Irvine AD, Alves AC, Groen-Blokhuis MM, Franke A, Ferreira M, Tamari M, Probst-Hensch N, Williams KL, Raby B, Burchard EG, Ober C, Barton S, Holloway J, Xu C, Thyssen J, Wang C, Jarvis D, Xiao F, Strachan DP, Brown SJ, Heinrich J, Evans DM, Weidinger S. A multi-ethnic genome-wide association study of 21 000 cases and 95 000 controls identifies 11 novel genetic variants associated with atopic dermatitis. Allergy 2015; 70(Suppl 101):82.
Background: Atopic dermatitis (AD) is a highly heritable common chronic inflammatory skin disease. Twenty-one genetic risk loci have been previously identified. The largest genome-wide association study (GWAS) to date included around 5000 cases and 20 000 controls (of only European origin) and identified 3 risk loci, putting AD some way behind many other complex common diseases that have been studied in much larger numbers and for which many more risk loci have been identified.
Method: We conducted the world’s largest GWAS of AD. Our discovery cohort consisted of 21 409 cases and 95 445 controls from 26 studies and used data imputed to the 1000 genomes reference panel (> 15 million variants). In addition to carrying out a fixed effects genome-wide meta-analysis of European individuals, we also included Japanese, Latino and African-American individuals in a multi-ethnic meta-analysis (using MANTRA software). Replication was sought in 30 582 cases and 226 518 controls from 17 studies.
Results: The discovery phase identified 27 loci associated with AD (11 novel). A gene-set enrichment analysis (using MAGENTA) identified 38 significantly enriched gene-sets (FDR < 0.05) out of a total of > 10 000 tested, and 9 additional SNPs (with P < 10-5) were taken forward to replication. Eleven of the 20 novel SNPs replicated and reached genome-wide significance. One particularly interesting association involved a series of SNPs near CD207, a gene selectively expressed in Langerhans cells (dendritic cells of the epidermis), putatively involved in antigen uptake and processing. These SNPs also showed strong association with CD207 expression in skin tissue in the MuTHER study (P = 2x10-10). Thus, our results suggest a possible role for genetic factors influencing epithelial dendritic cell function in the aetiology of AD. In addition to the novel loci we also identified four secondary signals at known loci. Furthermore our results show a substantial genetic overlap with other immune-mediated diseases, particularly inflammatory bowel disease (IBD). Thirty-nine of 163 SNPs robustly associated with IBD in a recent GWAS were at least nominally associated (P < 0.05) with AD in our analysis (34 with the same direction of effect).
Conclusion: Our results bring the total number of AD risk loci discovered to 31. All new loci include candidate genes with roles in regulating environmental sensing and adaptive immune responses, underscoring the important contribution of immune components to AD pathogenesis.