Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders

AI Summary

Largest GWAS of BPD: 12,339 cases, 1,041,717 controls; identified 11 independent loci and nine risk genes.
SNP heritability estimated at 17.3%; derived polygenic scores explain 4.6% of liability-scale phenotypic variance.
Genetic risk overlaps with PTSD, depression, ADHD, antisocial behaviour and self-harm; PGS associate with COPD and diabetes.

Nat Genet. 2026 Jul 20. doi: 10.1038/s41588-026-02654-3. Online ahead of print.

ABSTRACT

Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

PMID:42477112 | DOI:10.1038/s41588-026-02654-3

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