Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

Abstract

Background & aims: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities.

Methods: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10^-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance.

Results: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10^-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles.

Conclusions: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Keywords: Genetic Analysis; Risk Factor; SNP; Trans-Ethnic.

Figure 1

Experiment design flowchart. Two independent GWAS were performed and included 1258 cases/1678 controls (GWAS 1 genotyped on Illumina Omni2.5) and 1087 cases/3324 controls (GWAS 2 genotyped on Affymetrix Axiom Genome-Wide AFR 1 Array). After quality control and imputation based association analysis of CD, UC and IBD for each GWAS, a combined meta-analysis of observed and imputed SNPs identified 6 SNPs above genome threshold that are associated with UC in African Americans.

Figure 2

Figure 2A, 2B and 2C. Meta-analysis Manhattan plots for UC (2A), CD (2A) and IBD phenotypes, respectively. All SNPs are plotted according to their position on each chromosome on x-axis, against their association on y-axis. The red and blue lines indicate the genome-wide significance (p≤5×10⁻⁸) and the suggestive significance threshold (p ≤ 1×10⁻⁵), respectively. Genome-wide significant signals are labeled with corresponding gene names. The inset QQ plots shows the observed (y-axis) against the expected (x-axis) distribution of p-values under the null hypothesis with and without MHC.

Figure 3

LocusZoom plots of SNPs by chromosome position against –log₁₀ p-value for their genetic associations with IBD phenotype. Conditional regional plot for the HLA locus (chr6p21) for the IBD phenotype shows SNPs reaching genome-wide significance conditioned on SNP rs9270299 from UC analysis. The top SNP is highlighted in purple. The surrounding SNPs, shown within 500kb of the top SNP are color-coded to reflect their linkage disequilibrium in r² with the top SNP (see inset). Estimated recombination rates are plotted in pale blue to reflect local LD structure on secondary y-axis.

Figure 4

Figure 4(A–C): Odds ratios of SNPs maximally associated in Caucasians versus AAs for CD (4A), UC (4B) and IBD (4C) phenotypes. Red line: best-fitting least-squares regression line.