Abstract

Genetic risk is the earliest measurable contributor to diseases such as type 1 diabetes (T1D). Multiple groups have demonstrated that genetic (or polygenic) risk scores can quantify individual disease risks in a clinically significant way for complex diseases such as T1D. To date, genetic studies of T1D have been conducted primarily in European-ancestry populations and have identified over 40 susceptibility regions. Genetic risk estimates for T1D have been predominantly calculated from these findings. At the same time, there is also strong evidence that there are limitations in transferability of risk estimates from European-ancestry populations to African ancestry populations. Thus, establishing a better understanding of the genetic architecture of T1D in different populations is critical for appropriate applications of risk scores and eliminating health disparities. Aiming to close this gap in knowledge, we conducted the largest T1D association study in African-ancestry participants to date. Single nucleotide polymorphisms (SNPs) in the 12q13.2 region were associated with T1D in European- and African-ancestry populations. We used comparative mapping in the 12q13.2 region to fine-map this physically large and gene-rich T1D risk locus coupled with functional studies. Twelve SNPs (of 22 previously identified European credible SNPs) were nominally (P < 10-4) associated with T1D in African-ancestry populations. Using bioinformatics and ENCODE data, we identified four putative candidate causal SNPs. Using functional assays, we confirmed allele-specific protein binding for two of the 12q13.2 SNPs near RPS26 and IKZF4. While biological influence and detailed functional role of each risk variant will need to be characterized in future functional studies, incorporation of SNPs that capture genetic risk in genetically diverse populations provides insights into causality. Disclosure S. Onengut: None. H. Yang: None. R.R. Pickin: None. S.S. Rich: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

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