Functional annotation of sixty-five type-2 diabetes risk SNPs and its application in risk prediction

Abstract

Genome-wide association studies (GWAS) have identified more than sixty single nucleotide polymorphisms (SNPs) associated with increased risk for type 2 diabetes (T2D). However, the identification of causal risk SNPs for T2D pathogenesis was complicated by the factor that each risk SNP is a surrogate for the hundreds of SNPs, most of which reside in non-coding regions. Here we provide a comprehensive annotation of 65 known T2D related SNPs and inspect putative functional SNPs probably causing protein dysfunction, response element disruptions of known transcription factors related to T2D genes and regulatory response element disruption of four histone marks in pancreas and pancreas islet. In new identified risk SNPs, some of them were reported as T2D related SNPs in recent studies. Further, we found that accumulation of modest effects of single sites markedly enhanced the risk prediction based on 1989 T2D samples and 3000 healthy controls. The AROC value increased from 0.58 to 0.62 by only using genotype score when putative risk SNPs were added. Besides, the net reclassification improvement is 10.03% on the addition of new risk SNPs. Taken together, functional annotation could provide a list of prioritized potential risk SNPs for the further estimation on the T2D susceptibility of individuals.

The impact of phenotype, ethnicity and genotype on progression of type 2 diabetes mellitus

“…The effect of these SNPs is increasingly evaluated by constructing polygenic risk scores (PRS), whereby the individual risk alleles are summed to provide a genetic risk for each individual in a population. Studies of type 2 diabetes PRS showed a significant association with risk of type 2 diabetes after adjustment for other phenotypic factors, and a study conducted among Europeans demonstrated a 9.4‐fold risk for individuals in the upper vs lower 2.5% of the PRS …”

Polygenic risk scores predict diabetic complications and their response to therapy

“…Genetic information, with which one is born, offers a way to make early detection of risk. Genome-wide association studies (GWAS) identified multiple common variants associated with T2D 4-7 , renal 8,9 , cardiovascular diseases 10 , and hypertension 11 . Individually, these genetic variants account for only a small effect size but the combination of hundreds or thousands of them into polygenic risk scores (PRS) or genome-wide polygenic scores (GPS) was recently introduced to predict individual risk of diseases 12-15 including type 2 diabetes 16 .…”

Desenvolvimento de Escore de Risco Poligênico para Fenótipos Complexos: Pressão Arterial Sistólica

“…Felizmente, devido aos avanços contínuos fornecidos por estudos de associação genômica ampla (GWAS) e análises de sequenciamento de próxima geração, os dados genômicos e epigenéticos enriquecem o campo sobre o significado funcional dos SNPs de risco conhecidos. Embora a identificação do SNP de risco seja fundamental para ilustrar a relação entre as variantes humanas e o risco de distúrbios poligênicos, a maioria dos SNPs de risco reside em grandes íntrons ou distais aos exons codificadores, que no passado foram tratados como áreas de lixo no genoma humano [22]. Por isso, a anotação funcional é importante, fornecendo uma lista de SNPs de risco potencial, priorizados para a estimativa adicional da suscetibilidade a determinadas doenças nos indivíduos.…”