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

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.

Figure 1

Regional type 1 diabetes association plots for non-HLA risk loci identified in African Americans. LocusZoom plots for 2q33.2 (A); 6q22.32 (B); 10q23.31, observed association (rs10788599) is in close proximity (∼152 kb) but independent from reported intronic SNP (rs12416116) in European-ancestry populations (C); 11p15.5 (D); 12q13.2 (E); and 17q12 (F) (25). The most significant type 1 diabetes–associated SNP at each locus is plotted (purple). Each symbol on the plot represents a single SNP included in the type 1 diabetes association test (African-ancestry participants); the symbol color corresponds to the degree of LD, with the most significant SNP colored purple. The most significant type 1 diabetes–associated SNP reported in the study by Onengut-Gumuscu et al. (6) is indicated with a yellow-colored star with the exception of 12q13.2, where rs705705 is the index SNP for both populations, indicated with a purple diamond. Type 1 diabetes 99% credible SNPs identified in European-ancestry populations that passed quality control in African-ancestry data are marked with triangles, and all other SNPs are marked with a circle.

Figure 2

Type 1 diabetes risk prediction in African-ancestry subjects using a GRS. The red curve is for the prediction using an African-ancestry GRS (AA GRS), and the black curve is for the prediction using a European-ancestry GRS (EUR GRS) (7).