Altered
vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic
encephalopathy, which can be treated with high doses of
vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic
generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence
vitamin B6 metabolite levels. Such an influence would suggest that
vitamin B6 could play a role in GGE
therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of
vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence
vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of
vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with
vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of
vitamin B6 in GGE, although these findings require further replication.