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

• Published in: Diabetes care Vol. 42; no. 3; pp. 406 - 415
• Main Authors: Onengut-Gumuscu, Suna, Chen, Wei-Min, Robertson, Catherine C., Bonnie, Jessica K., Farber, Emily, Zhu, Zhennan, Oksenberg, Jorge R., Brant, Steven R., Bridges, S. Louis, Edberg, Jeffrey C., Kimberly, Robert P., Gregersen, Peter K., Rewers, Marian J., Steck, Andrea K., Black, Mary H., Dabelea, Dana, Pihoker, Catherine, Atkinson, Mark A., Wagenknecht, Lynne E., Divers, Jasmin, Bell, Ronny A., Erlich, Henry A., Concannon, Patrick, Rich, Stephen S.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.03.2019
• Subjects: Alleles; Black People - genetics; Black People - statistics & numerical data; Case-Control Studies; Clinical Care/Education/Nutrition/Psychosocial Research; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - ethnology; Diabetes Mellitus, Type 1 - genetics; DQA1 protein; Drb1 protein; Female; Gene polymorphism; Genetic diversity; Genetic Predisposition to Disease; Genetic Testing - methods; Genetic Testing - standards; Genetic variance; Genetics; Genome-Wide Association Study; Genomes; Haplotypes; Health risk assessment; Health risks; Histocompatibility antigen HLA; HLA-D Antigens - genetics; HLA-DQ alpha-Chains - genetics; HLA-DQ beta-Chains - genetics; HLA-DRB1 Chains - genetics; Humans; Loci; Male; Polymorphism; Polymorphism, Single Nucleotide; Population studies; Predictive Value of Tests; Race; Regression analysis; Regression models; Research Design; Risk; Risk Factors; Single-nucleotide polymorphism; White People - genetics; United States > US
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc18-1727

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. 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 ( < 5.0 × 10 ) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci ( < 2.79 × 10 ). African-specific (HLA- *03:01-HLA- *02:01) and known European-ancestry HLA haplotypes (HLA- *03:01-HLA- *05:01-HLA- *02:01, HLA- *04:01-HLA- *03:01-HLA- *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. 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.