EPA-0871 – Genome-wide Association Study of NMDA Receptor Coagonists in Cerebrospinal Fluid and Plasma Identifies Metabolic and Transporter Pathways

Abstract

The N-methyl-D-aspartate receptor (NMDAR) co-agonists Glycine, D-Serine, L-Proline and possibly D-Alanine play crucial roles in NMDARdependent neurotransmission and were shown to mediate susceptibility to neuropsychiatric disorders. Cerebrospinal fluid (CSF) has not been targeted in genome-wide associations studies (GWASs) of NMDAR co-agonists. Moreover, mechanisms underlying amino acid enantiomer concentration variations remain elusive although heritability estimates suggest amino acids in other body fluid compartments are under genetic control.

We conducted GWASs of Proline, Serine, Glycine and Alanine enantiomer concentrations (and ratios) in the plasma and cerebrospinal fluid (CSF) of healthy human subjects (N=414).

A number of metabolic QTLs were identified. Variants on 22q11.2, located 35kb from PRODH, were associated with L-Proline in plasma (standardized β = 0.29; P = 6.38 × 10⁻¹⁰). The missense variant rs17279437 in the Proline transporter SLC6A20 associated with both L-Proline in CSF (β = 0.28; P = 9.68 × 10⁻⁹) and the L-Proline plasma-CSF ratio (β = −0.30; P = 2.88 × 10⁻⁹). Suggestively significant association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (β = −0.28; P = 9.08 × 10⁻⁸).

These metabolic QTL findings portend substantial power of GWASs targeting CSF constituents in neurologically healthy human subjects. We demonstrate how L and D-enantiomer quantitative analyses deepen the understanding of NMDAR co-agonist metabolic and transporter mechanisms. The detected L-Proline QTLs on chromosome 22q11 and 3p21.31 potentially set a stage for further genetic and pharmacological studies in patients suffering 22q11 deletion syndrome and hyperprolinemia.