SHARED GENETIC ARCHITECTURE AND DIRECTIONAL ASSOCIATIONS BETWEEN ATTENTION-DEFICIT/HYPERACTIVITY AND BORDERLINE PERSONALITY DISORDERS: AN INTEGRATIVE GENOMIC ANALYSIS
- 1Azienda Sanitaria Provinciale di Vibo Valentia, Ospedale Jazzolino
Abstract
Background: Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) frequently co-occur, but the contributions of shared genetic susceptibility and directional associations remain unclear. Methods: We analyzed European-ancestry GWAS summary statistics for ADHD (38,691 cases; 186,843 controls) and BPD (12,339 cases; 1,041,717 controls). Linkage disequilibrium score regression, conjunctional false discovery rate (conjFDR), bidirectional Mendelian randomization (MR), MR-LAP, CAUSE, colocalization, and SuSiE fine-mapping assessed genetic overlap and directional associations. Results: ADHD and BPD showed substantial genetic correlation (r_g = 0.733). ConjFDR identified 48 shared loci, of which 36 (75%) showed consistent effect directions across independent phenotype-specific comparisons. Functional annotation highlighted axon guidance, oxidative phosphorylation, and a developing midbrain cell-type signature. ADHD-to-BPD MR supported a positive association (22 instruments; IVW-beta = 0.487, SE = 0.082, p = 3.27 x 10^-9), persisting after outlier removal, MR-LAP correction, and exclusion of two instruments indexing colocalized loci. Reverse MR was also positive (five instruments; IVW-beta = 0.303, SE = 0.112, p = 6.83 x 10^-3), but showed heterogeneity and sensitivity to individual variants. CAUSE favored directional over sharing-only models for ADHD-to-BPD (Delta ELPD = 6.98; p = 7.3 x 10^-8) and BPD-to-ADHD (Delta ELPD = 5.92; p = 6.2 x 10^-5). Colocalization and SuSiE supported shared signals at loci indexed by rs17576773 and rs9969232 for ADHD-to-BPD and rs4727799 in the reverse direction. Conclusions: ADHD and BPD share extensive genetic susceptibility. Although CAUSE favored directional models in both directions, evidence across MR approaches was more consistent for ADHD-to-BPD. Shared genetic mechanisms and residual pleiotropy limit causal interpretation.
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BibTeX
@misc{gorgone2026shared,
title = {{SHARED GENETIC ARCHITECTURE AND DIRECTIONAL ASSOCIATIONS BETWEEN ATTENTION-DEFICIT/HYPERACTIVITY AND BORDERLINE PERSONALITY DISORDERS: AN INTEGRATIVE GENOMIC ANALYSIS}},
author = {G. Gorgone and C. Galati and S. Ciappina},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.26367465},
url = {https://www.medrxiv.org/content/10.64898/2026.11.06.26367465v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - SHARED GENETIC ARCHITECTURE AND DIRECTIONAL ASSOCIATIONS BETWEEN ATTENTION-DEFICIT/HYPERACTIVITY AND BORDERLINE PERSONALITY DISORDERS: AN INTEGRATIVE GENOMIC ANALYSIS
AU - G. Gorgone
AU - C. Galati
AU - S. Ciappina
PY - 2026
DA - 2026/11/06
PB - medRxiv
DO - 10.64898/2026.11.06.26367465
UR - https://www.medrxiv.org/content/10.64898/2026.11.06.26367465v1
AB - Background: Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) frequently co-occur, but the contributions of shared genetic susceptibility and directional associations remain unclear. Methods: We analyzed European-ancestry GWAS summary statistics for ADHD (38,691 cases; 186,843 controls) and BPD (12,339 cases; 1,041,717 controls). Linkage disequilibrium score regression, conjunctional false discovery rate (conjFDR), bidirectional Mendelian randomization (MR), MR-LAP, CAUSE, colocalization, and SuSiE fine-mapping assessed genetic overlap and directional associations. Results: ADHD and BPD showed substantial genetic correlation (r_g = 0.733). ConjFDR identified 48 shared loci, of which 36 (75%) showed consistent effect directions across independent phenotype-specific comparisons. Functional annotation highlighted axon guidance, oxidative phosphorylation, and a developing midbrain cell-type signature. ADHD-to-BPD MR supported a positive association (22 instruments; IVW-beta = 0.487, SE = 0.082, p = 3.27 x 10^-9), persisting after outlier removal, MR-LAP correction, and exclusion of two instruments indexing colocalized loci. Reverse MR was also positive (five instruments; IVW-beta = 0.303, SE = 0.112, p = 6.83 x 10^-3), but showed heterogeneity and sensitivity to individual variants. CAUSE favored directional over sharing-only models for ADHD-to-BPD (Delta ELPD = 6.98; p = 7.3 x 10^-8) and BPD-to-ADHD (Delta ELPD = 5.92; p = 6.2 x 10^-5). Colocalization and SuSiE supported shared signals at loci indexed by rs17576773 and rs9969232 for ADHD-to-BPD and rs4727799 in the reverse direction. Conclusions: ADHD and BPD share extensive genetic susceptibility. Although CAUSE favored directional models in both directions, evidence across MR approaches was more consistent for ADHD-to-BPD. Shared genetic mechanisms and residual pleiotropy limit causal interpretation.
ER -