Next Generation Exome Sequence Analysis of Human Blood Group Antigens

The ABO gene encodes a glycosyltransferase which adds sugar moieties (a-N-acetylgalactosamune for A and α -D-galactose for B) to a substrate known as the H antigen. Variants in the ABO gene affect the function of glycosyltransferases at the molecular level by altering the specificity of this enzyme. Beyond encoding the major blood groups, variation in the ABO gene has been linked to clinically relevant phenotypes such as cardiovascular disease, pancreatic cancer risk, and susceptibility to certain infectious diseases.

Here we use a large exome sequencing dataset from nearly ~7,000 well-phenotyped individuals (including both African-Americans and Caucasians) to identify and characterize known and novel alleles and haplotypes in the ABO gene. Roughly 100 of these ~7,000 individuals have corresponding data from hemaaglutination assays, the current clinical standard for determining ABO blood group status.

Thus far we have identified 51 non-synonymous variants in total in the ABO gene. 43 missense variants, 18 of those being novel. 2 nonsense variants 1 of those being novel. 1 novel splice site variant, and 5 insertion or deletions, 4 of those being novel. All of the novel variants are either singletons or occur at a minor allele frequency (MAF) of less than 1%.

Our ABO-phased haplotype calls demonstrate the feasibility of blood typing using sequence data. We also demonstrate that ~25% of people have novel ABO alleles. This represents a useful set of variants to explore functional significance of variation in ABO.