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

Gastroenterology. 2017 Jan;152(1):206-217.e2. doi: 10.1053/j.gastro.2016.09.032. Epub 2016 Sep 28.

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.

Publication types

  • Meta-Analysis
  • Multicenter Study

MeSH terms

  • Adenylyl Cyclases / genetics
  • African Americans / genetics*
  • Case-Control Studies
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Colitis, Ulcerative / genetics*
  • Crohn Disease / genetics*
  • European Continental Ancestry Group / genetics
  • GPI-Linked Proteins / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Genotyping Techniques
  • HLA-DQ alpha-Chains / genetics
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Interleukin-12 Subunit p40 / genetics
  • KCNQ2 Potassium Channel / genetics
  • Polymorphism, Single Nucleotide
  • Receptors, CXCR6
  • Receptors, Chemokine / genetics
  • Receptors, Interleukin / genetics
  • Receptors, Prostaglandin E, EP4 Subtype / genetics
  • Receptors, Virus / genetics
  • Repressor Proteins / genetics*
  • Sorting Nexins / genetics
  • Tenascin / genetics
  • Ubiquitin Thiolesterase / genetics*

Substances

  • CXCR6 protein, human
  • Cell Adhesion Molecules, Neuronal
  • GPI-Linked Proteins
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • HLA-DRB1 Chains
  • IL12B protein, human
  • IL23R protein, human
  • Interleukin-12 Subunit p40
  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • PTGER4 protein, human
  • Receptors, CXCR6
  • Receptors, Chemokine
  • Receptors, Interleukin
  • Receptors, Prostaglandin E, EP4 Subtype
  • Receptors, Virus
  • Repressor Proteins
  • SNX20 protein, human
  • Sorting Nexins
  • Tenascin
  • USP25 protein, human
  • ZNF649 protein, human
  • limbic system-associated membrane protein
  • Ubiquitin Thiolesterase
  • Adenylyl Cyclases
  • adenylate cyclase 3