Multi-ancestry Genome-Wide Association Meta-Analysis Identifies Novel Loci in Atopic Dermatitis

Atopic dermatitis (AD) is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to AD genetic association studies are poised to boost power to detect genetic signal and identify ancestry-specific loci contributing to AD risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve AD cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls. We report 101 genomic loci associated with AD, including 15 loci that have not been previously associated with AD or eczema. Fine-mapping, QTL colocalization, and cell-type enrichment analyses identified genes and cell types implicated in AD pathophysiology. Functional analyses in keratinocytes provide evidence for genes that could play a role in AD through epidermal barrier function. Our study provides new insights into the etiology of AD by harnessing multiple genetic and functional approaches to unveil the mechanisms by which AD-associated variants impact genes and cell types. Datasets in this collection include:

• sc-RNAseq dataset is composed of samples from 96 skin biopsies from seven body sites (face, scalp, axilla, palmoplantar, arm, leg, and back).
• Cis eQTLs maps are derived from keratinocyte cell lines from N=50 subjects, for which RNA-Seq profiles and genotype data were generated. Cell lines were subjected to 8 different conditions implicated in AD pathogenesis: no stimulation, TNF (10ng/ml), IL-4 (10ng/ml), IL-13 (10ng/ml), IL-17A (10ng/ml), IL-17A+TNF, IFNa (5ng/ml), IFNg (5ng/ml).
• Gene expression changed occurring in the formation of 3-D human epidermal raft cultures. Normal human epidermal keratinocytes were isolated from epidermis (n=3) and grown using J2-3T3 mouse fibroblasts as a feeder layer originally described by Rheinwald and Green53.
• GWAS meta-analysis on 12 cohorts comprising a total of 56,146 AD cases and 602,280 controls of European (EUR), Asian (ASN), African (AFR), American (AMR) and admixed ancestries. Ancestry-specific GWAS of EUR, EAS and AFR cohorts. Genomic locations provided for human genome build 38.