Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score

Diabetes Care. 2019 Mar;42(3):406-415. doi: 10.2337/dc18-1727. Epub 2019 Jan 18.

Abstract

Objective: Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS.

Research design and methods: We generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5).

Results: African-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts.

Conclusions: Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • African Continental Ancestry Group / genetics*
  • African Continental Ancestry Group / statistics & numerical data
  • Alleles
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / ethnology*
  • Diabetes Mellitus, Type 1 / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing* / methods
  • Genetic Testing* / standards
  • Genome-Wide Association Study
  • HLA-D Antigens / genetics*
  • HLA-DQ alpha-Chains / genetics
  • HLA-DQ beta-Chains / genetics
  • HLA-DRB1 Chains / genetics
  • Haplotypes
  • Humans
  • Male
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Research Design
  • Risk Factors

Substances

  • HLA-D Antigens
  • HLA-DQ alpha-Chains
  • HLA-DQ beta-Chains
  • HLA-DQA1 antigen
  • HLA-DQB1 antigen
  • HLA-DRB1 Chains