Abstract
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.
Highlights
Treatment with vitamin B6 can control seizures in a subset of children with early-onset intractable seizures [1]
We found that genetic generalized epilepsy (GGE)-associated SNPs alter expression of PNPO in the dorsolateral prefrontal cortex [14], suggesting that altered vitamin B6 metabolism might be involved in the pathophysiology of GGE
We used default settings of PRSice to perform polygenic risk scoring (PRS) analyses to establish whether people with GGE have different pyridoxine metabolism PRS scores compared to controls
Summary
Treatment with vitamin B6 can control seizures in a subset of children with early-onset intractable seizures [1]. Such vitamin B6-responsive epilepsy can be caused by mutations in a number of genes, pyridoxal-5′-phosphate oxidase (PNPO [2,3,4,5]), which is essential to convert pyridox(am)ine-5′-phosphate into the active form of vitamin B6, pyridoxal-5′-phosphate (PLP). PLP levels are reduced in some patients with common forms of epilepsy [7,8], possibly due to the effects of antiepileptic drugs [9,10]. PLP treatment can reduce seizure frequency in some refractory epilepsy patients without documented pathogenic variants [7,13]
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