Glutamatergic Target Genes Show Disproportionate Contribution to Borderline Personality Disorder Risk: Multi-Method Analysis of GWAS Data

Background. Borderline personality disorder (BPD) features prominent emotional lability, impulsive behaviour, and unstable relationships. Neuroimaging and spectroscopy studies point to excess glutamatergic activity and faulty synaptic plasticity in key cortico-limbic circuits, yet genome-wide investigations have not tested whether common risk alleles concentrate in glutamate-related genes.Methods. We re-examined publicly available genome-wide association summary statistics from a European-ancestry BPD cohort (effective N ≈ 29,061) that excluded cases with bipolar disorder or schizophrenia. Gene-based tests and competitive gene-set analyses were run in MAGMA. The primary set comprised 23 prespecified glutamatergic genes—ionotropic receptor subunits, plasticity mediators, transporters, and metabolic regulators. An expanded 130-gene plasticity panel and two negative-control sets (monoaminergic and housekeeping genes) were analysed in parallel. To quantify over-representation of signal within target regions, we calculated χ² enrichment for all single-nucleotide polymorphisms (SNPs) mapped to each target gene.Results. Competitive testing showed nominal enrichment for the target-gene set (one-sided p = 0.049) and for the broader plasticity panel (p = 0.045); neither control set was significant. Annotation enrichment revealed a 12 % inflation of mean χ² within target-gene loci (p = 3.2 × 10⁻⁴). The signal was driven by SNPs in glutamate transporters (42 % inflation; p = 7.4 × 10⁻¹⁸), NMDA-receptor genes (26 %; p = 3.8 × 10⁻⁸) and metabolic modifiers (34 %; p = 7.0 × 10⁻³).Conclusions. Common variants that influence glutamate clearance and NMDA signalling account for a disproportionate share of polygenic risk in BPD when cases with psychotic or bipolar features are removed. These genetic data strengthen mechanistic models that link glutamatergic dysregulation to BPD psychopathology and support continued development of NMDA/AMPA-modulating therapeutics for this condition.