@article{847d9ff1abc7429ababd89ece2e5c70a,
title = "Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy",
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.",
keywords = "Genetics, GGE, GWAS, Pharmacogenetics, Pyridoxine, SNP",
author = "Remi Stevelink and Faith Pangilinan and Jansen, {Floor E.} and Braun, {Kees P.J.} and Molloy, {Anne M.} and Brody, {Lawrence C.} and Koeleman, {Bobby P.C.}",
note = "Funding Information: We are grateful to the Ming Fund for supporting this project. This work was also supported by the Intramural Research Program of the National Human Genome Research Institute. Parts of the analysis of this work were performed on resources of the High Performance Center of the University of Luxembourg and Elixir-Luxembourg. Some of the data reported in this paper were collected as part of a project undertaken by the International League against Epilepsy (ILAE) and some of the authors are experts selected by the ILAE. Opinions expressed by the authors, however, do not necessarily represent the policy or position of the ILAE. Declaration of Competing Interest, None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Funding Information: We are grateful to the Ming Fund for supporting this project. This work was also supported by the Intramural Research Program of the National Human Genome Research Institute . Parts of the analysis of this work were performed on resources of the High Performance Center of the University of Luxembourg and Elixir-Luxembourg. Some of the data reported in this paper were collected as part of a project undertaken by the International League against Epilepsy (ILAE) and some of the authors are experts selected by the ILAE. Opinions expressed by the authors, however, do not necessarily represent the policy or position of the ILAE. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = dec,
day = "1",
doi = "10.1016/j.ymgmr.2019.100518",
language = "English",
volume = "21",
}