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Open AccessArticle

The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma

1
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA
2
Section Metabolic Diagnostics, Department of Genetics, University Medical Center (UMC), 3584 EA Utrecht, The Netherlands
3
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center (UMC), 3584 CG Utrecht, The Netherlands
4
Department of Translational Neuroscience, Human Neurogenetics Unit, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMC), 3584 CG Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Amsterdam UMC, VU Medical Center, Department of Clinical Chemistry, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Received: 3 December 2018 / Revised: 13 December 2018 / Accepted: 14 December 2018 / Published: 22 December 2018
(This article belongs to the Section Human Genomics and Genetic Diseases)
The active form of vitamin B6, pyridoxal phosphate (PLP), is essential for human metabolism. The brain is dependent on vitamin B6 for its neurotransmitter balance. To obtain insight into the genetic determinants of vitamin B6 homeostasis, we conducted a genome-wide association study (GWAS) of the B6 vitamers pyridoxal (PL), PLP and the degradation product of vitamin B6, pyridoxic acid (PA). We collected a unique sample set of cerebrospinal fluid (CSF) and plasma from the same healthy human subjects of Dutch ancestry (n = 493) and included concentrations and ratios in and between these body fluids in our analysis. Based on a multivariate joint analysis of all B6 vitamers and their ratios, we identified a genome-wide significant association at a locus on chromosome 1 containing the ALPL (alkaline phosphatase) gene (minimal p = 7.89 × 10−10, rs1106357, minor allele frequency (MAF) = 0.46), previously associated with vitamin B6 levels in blood. Subjects homozygous for the minor allele showed a 1.4-times-higher ratio between PLP and PL in plasma, and even a 1.6-times-higher ratio between PLP and PL in CSF than subjects homozygous for the major allele. In addition, we observed a suggestive association with the CSF:plasma ratio of PLP on chromosome 15 (minimal p = 7.93 × 10−7, and MAF = 0.06 for rs28789220). Even though this finding is not reaching genome-wide significance, it highlights the potential of our experimental setup for studying transport and metabolism across the blood–CSF barrier. This GWAS of B6 vitamers identifies alkaline phosphatase as a key regulator in human vitamin B6 metabolism in CSF as well as plasma. Furthermore, our results demonstrate the potential of genetic studies of metabolites in plasma and CSF to elucidate biological aspects underlying metabolite generation, transport and degradation. View Full-Text
Keywords: genome wide association study; vitamin B6; cerebrospinal fluid; plasma genome wide association study; vitamin B6; cerebrospinal fluid; plasma
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Olde Loohuis, L.M.; Albersen, M.; De Jong, S.; Wu, T.; Luykx, J.J.; Jans, J.J.M.; Verhoeven-Duif, N.M.; Ophoff, R.A. The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma. Genes 2019, 10, 8.

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