Joint genotype and ancestry analysis identify novel loci associated with atopic dermatitis in African American population

Abstract

Atopic dermatitis (AD) is a chronic itchy inflammatory disease of the skin. Genetic studies have identified multiple risk factors linked to the disease; however, most of the studies have been derived from European and East Asian populations. The admixed African American (AA) genome may provide an opportunity to discovery ancestry-specific loci involved in AD susceptibility. Herein, we present joint analysis of ancestry and genotype effects followed by validation using differential gene expression analysis on AD using 726 AD-affected individuals and 999 non-AD control individuals from the AA population, genotyped using Multi-Ethnic Global Array (MEGA) followed by imputation using the Consortium on Asthma among African Ancestry Populations in the Americas (CAAPA) reference panel. The joint analysis identified two novel AD-susceptibility loci, rs2195989 in gene ANGPT1 (8q23.1) and rs62538818 in the intergenic region between genes LURAP1L and MPDZ (9p23). Admixture mapping (AM) results showed potential genomic inflation, and we implemented genomic control and identified five ancestry-of-origin loci with European ancestry effects. The multi-omics functional prioritization of variants in AM signals prioritized the loci SLAIN2, RNF39, and FOXA2. Genome-wide association study (GWAS) identified variants significantly associated with AD in the AA population, including SGK1 (rs113357522, odds ratio [OR] = 2.81), EFR3A (rs16904552, OR = 1.725), and MMP14 (rs911912, OR = 1.791). GWAS variants were common in the AA but rare in the European population, which suggests an African-ancestry-specific risk of AD. Four genes (ANGPT1, LURAP1L, EFR3A, and SGK1) were further validated using qPCR from AD and healthy skin. This study highlighted the importance of genetic studies on admixed populations, as well as local ancestry and genotype-ancestry joint effects to identify risk loci for AD.

Keywords: African American; admixed population; admixture mapping; atopic dermatitis; fine mapping; genome-wide association; joint analysis; local and global ancestry.

Graphical abstract

Figure 1

Ancestry estimation (A) Distribution of global ancestry for two reference populations (CEU and YRI) and samples in case and control cohorts (orange, European ancestry; green, African ancestry). (B) Histogram showing the distribution of African ancestry in sample. (C) Correlation between African ancestry and PC1.

Figure 2

Miami plot of AM result The upper section shows results from case-only analysis. The lower section shows results from case-control analysis. The x axis represents chromosome position. The y axis represents p value. Orange horizontal line represent genome-wide significance at p < 1.47E−5 with adjustment for genomic inflation. Gray dashed horizontal lines represent suggestive association at p-value < 1E-3.

Figure 3

AD GWAS results (A) Manhattan plot of AD GWAS. Gray horizontal lines represent significance signals at p < 1E−5. (B) QQ plot. λ = 1.013 is the genomic inflation factor.

Figure 4

Regional plot of region with significant BMIX SNPs (A) SNP rs2195989 at chromosome 8q23.1. (B) SNP rs62538818 at chromosome 9p23. The upper part shows the results from AM analysis (red dots, case-only AM result; green dot, case-control AM result). The middle section shows local ancestry distribution in cases (red), control (green), and global ancestry (orange). The lower section shows GWAS results. Vertical dashed line marks the BMIX SNP.

Figure 5

Replication of existing AD-risk variants reported in GWAS Catalog The outer track shows the AD-risk SNPs from the GWAS Catalog and the purple dots with varying shade represent the p value. Second layer showed the GWAS p value of the SNPs with dark red segments showing the significant replication at p < 2.9E−4 and lighter red segments showing marginal replication at p < 0.05. The innermost layer shows the AM case-only p value with dark orange segments representing significant replication.

Figure 6

Expression levels of select AD-associated genes (A) SGK1, (B) EFR3A, (C) ANGPT1, and (D) LURAP1L. All genes were upregulated in AD patients when compared to healthy control individuals. Experiments were done on RNA isolated from blood using three healthy control individuals and six participants diagnosed with AD. ∗p < 0.05, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001.