Environmental and genetic risk factors contribute to the development of borderline personality disorder (BPD). We conducted the largest GWAS of BPD to date, meta-analyzing data from 12,339 cases and 1,041,717 controls of European ancestry, and identified six independent associated genomic loci. Gene-based analysis identified nine risk genes. We observed a single-nucleotide polymorphism (SNP) heritability of 17.3% and derived polygenic scores (PGS) predicted 4.6% of the phenotypic variance in BPD case-control status. BPD showed the strongest positive genetic correlations with GWAS of posttraumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide association analyses using BPD-PGS confirmed these associations and revealed associations of BPD risk with general medical conditions including obstructive pulmonary disease and diabetes. The present genetic analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

Ole A Andreassen is a consultant to Cortechs.ai and Precision Health and has received speakers honoraria from Lundbeck, Janssen, Sunovion, and Otsuka. Soren Brunak has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK abello A/S, Eli Lilly and Co and managing board memberships in Proscion A/S and Intomics A/S. James L Kennedy is a Scientific Advisory Board member of Myriad Neuroscience. Richard Musil has received financial research support from Boehringer-Ingelheim and Otsuka Pharmaceuticals. He has received speakers honoraria from Otsuka Pharmaceuticals and Lundbeck and is a member of the advisory board of Boehringer-Ingelheim. Frank Padberg is a member of Scientific Advisory Boards of Brainsway Inc., Jerusalem, Israel, and of Sooma, Helsinki, Finland. He has received speakers honoraria from Mag&More GmbH, the neuroCare Group, Munich, Germany, and Brainsway Inc. J. Antoni Ramos-Quiroga was on the speakers bureau and/or acted as a consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubio, Uriach, Technofarma and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubio, Takeda, Bial, and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas, and Rubio. Claudia Schilling received lecturer fees from Idorsia Pharmaceuticals GmbH (2024).

Individual-level data are not publicly available due to privacy or ethical restrictions. The results of the meta-analysis data will be publicly available for download upon publication of the manuscript. The GWAS summary statistics of other traits and disorders used for analyses in this study are publicly available. In case they include data from 23andMe (e.g., Big Five personality traits), they can be made available to qualified investigators, if they enter into an agreement with 23andMe that protects participant confidentiality.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The following ethics committee/IRB gave ethical approval for this work: Ethics Committee of the Medical Faculty Mannheim of the University of Heidelberg; Ethical Board of Charite - Universitaetsmedizin Berlin, Berlin, Germany Ethics Committee of the Medical Faculty Mannheim of the University of Heidelberg (reference: 2011-22N-MA) Ethics Committee of the Medical Faculty Mannheim of the University of Heidelberg (reference: 2014-550N-MA) Ethical Board of Charite - Universitaetsmedizin Berlin, Berlin, Germany Ethics committee of the University of Tuebingen Ethics Committee of the Medical Faculty Mannheim of the University of Heidelberg (reference: 2011-315N-MA) Ethics committe of the MEdical Faculty of LMU Munich, (reference number 713-15) Ethics Comitee NorthWest and Central Switzerland (EKNZ) Ethic Committee of the Republic and Canton of Geneva; ID PB_2017-00061 Medical Ethical Committee Academic Hospital Maastricht & Maastricht University, the Netherlands (reference METC 09-3-044) Murdoch University Human Research Ethics Committee, Australia (reference 2010/217) NRES Committee London - Camberwell St Giles, UK (reference 13/LO/1631) Ethik-Kommission Albert-Luedwigs-Universitaet Freiburg, Germany (reference 303/09) Ethik-Kommission Universitaet zu Luebeck, Germany (reference 09-094) Ethics Committee and Committee for the Human Rights of Eginition Hospital Athens, Greece (reference 185, 20/3/2014) Protocols were approved by the Centre for Addiction (CAMH) and Mental Health and St. Michaels Hospital Research Ethics Boards in Toronto, Ontario, Canada Ethics approval to conduct this study was approved by the research ethics boards at CAMH in Toronto, Ontario on May 15, 2014 (#026/2014) and at Simon Fraser University in Burnaby, British Columbia on August 28, 2015 (#2014 s0263) both in Canada. In September 2015, an ethical amendment was approved for recruitment from the existing study to participate in the genetics sub-project, which had a separate consent form and process. Ethical Board: Hospital de la Santa Creu I Sant Pau Clinical Research Ethics Committee Hospital Universitari Vall dHebron, Barcelona Regional Committees for Medical and Health Research Ethics (reference Regional Committees for Medical and Health Research Ethics (reference 12656) Regional Committees for Medical and Health Research Ethics (reference Regional Committees for Medical and Health Research Ethics (reference 12656) The activities of the Douglas Bell-Canada Brain Bank are regulated through an authorization of the Douglas Institute Ethics Research Board for tissue banking. Institutional Review Board/ Vanderbilt University Medical Center Danish National Committee on Health Research Ethics (Approval Nr. NVK-18038012 for CHB; NVK-1700407 for DBDS National Bioethics Committee of Iceland (Approval no: VSNb2016040011/03.01) Estonian Committee on Bioethics and Human Research (1.1-12/624) Regional Committee for Medical and Health Research Ethics (ref. 2015/575) Regional Committee for Medical and Health Research Ethics (ref. 14140 and 2016/1226) The study was reviewed and approved by Mayo Clinics Institutional Review Board (Mayo Clinic IRB approval 19-006227) London - Fulham Research Ethics Committeeon 21st August 2018 (REC reference: 18/LO/1218) Research Tissue Bank (RTB) approval from North West Multi-centre Research Ethics Committee (MREC) Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. (details see Supplementary methods) Ethics Committee of the Hospital Universitari Sant Joan de Reus (06/2000 for case samples; 06/1998 and 10/2000 for control samples)

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Individual-level data are not publicly available due to privacy or ethical restrictions. The results of the meta-analysis data will be publicly available for download upon publication of the manuscript. The GWAS summary statistics of other traits and disorders used for analyses in this study are publicly available. In case they include data from 23andMe (e.g., Big Five personality traits), they can be made available to qualified investigators, if they enter into an agreement with 23andMe that protects participant confidentiality.

https://research.23andme.com/dataset-access/