Phenome-wide association study and functional annotation of hemoglobin A1c-associated variants in African populations

Background: Glycated hemoglobin (HbA1c) measures the average blood sugar level over the past three months. As a vital biomarker of blood glucose levels, it is used to diagnose Type-2 diabetes mellitus (T2D) and monitor glycemic control. A heritability estimate of 47% to 59% suggests that about half of the variation in HbA1c levels can be attributed to genetic factors. Despite African populations being the most genetically diverse and unique for fine-mapping, there is a paucity of data on the genetic drivers of HbA1c in African individuals. In this study, we performed functional annotation and a Phenome-Wide Association Study (PheWAS) of HbA1c-associated variants in two African populations. Method: In this study, we utilized summary statistics of the HbA1c GWAS meta-analysis of 7,526 individuals from South Africa and Uganda to conduct a PheWAS using GWASATLAS. We also performed a functional analysis using the functional mapping and annotation (FUMA) tool. Single nucleotide polymorphisms (SNPs) were prioritized using the SNP2GENE function, while the gene expression patterns and shared molecular functions were explored in the GENE2FUNC. Result: Three genome-wide significant loci were identified with the lead SNPs: rs6724428, rs148228241, and rs8045544 – mapped to GULP1 , HBA1 , and ITFG3 genes, respectively. The minor allele frequencies of rs148228241 (0.07) and rs8045544 (0.19) are rare or non-existent in non-African populations. Both rs8045544 and rs148228241 are significantly associated with the mean corpuscular hemoglobin concentration (MCHC). A lower MCHC is associated with alpha thalassaemia, resulting from deletions in HBA1 and HBA2 genes. Such deletions are prevalent in malaria-endemic regions of Africa due to their selective survival advantage. The rs6724428 variant is associated with skeletal functions, reflecting the link between glucose metabolism and bone mineral density. Discussion: Our findings highlight the interplay between glucose metabolism, erythropoiesis, and skeletal health. The significant associations of HbA1c-variants with both skeletal function and MCHC underscore the potential of these variants to impact broader physiological processes. A large-scale study of African individuals will be essential to unravel genetic variants influencing HbA1c.

Additional Information

Supplementary material include: Quantile-Quantile (Q-Q) Plot of GWAS P-value (S1 Fig), differentially expressed genes across GTEx v8 tissue types (S2 Fig), Lead SNPs from 189 genome-wide significant (P-value <5 × 10−8) SNPs (S1 Table), GWAS Metaanalysis Independent Significant SNPs (S2 Table), Annotation of GWAS Metaanalysis Significant SNPs (S3 Table), PheWAS results for the rs6724428 at the GULP1 locus (S4 Table), PheWAS results for the rs8045544 at the ITFG3 locus (S5 Table), and PheWAS results for the rs148228241 at the HBA1 locus (S6 Table).

Keywords

Single nucleotide polymorphisms; Genome-wide association studies; HbA1c; Genetic loci; Gene expression; Genome annotation; Metaanalysis; Population genetics