Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia

Stephanie H Witt ,Scott D Gordon ,Joanna Hauser ,Caroline M Nievergelt ,Andrew Bethell ,Enda M Byrne ,Jana Strohmaier ,Marion Leboyer ,Cornelia E Schwarze ,Brenda W J H Penninx ,Manolis Kogevinas ,Bruno Étain ,Arianna Di Florio ,Philip B Mitchell ,Norbert Dahmen ,George Kirov ,Eco J C De Geus ,Sarah E Bergen ,Sven Cichon ,Per Hoffmann ,Sascha Fischer ,Peter Holmans ,Markus M Nöthen ,Franziska Degenhardt ,René S Kahn ,Elliot S Gershon ,Martina Bauer ,Susanne Lucae ,Katherine Gordon‐Smith ,Jouke‐Jan Hottenga ,Dan Rujescu ,Andrew Mcquillin ,Ian Jones ,David Curtis ,Sarah Knott ,Maria Grigoroiu-Serbǎnescu ,Klaus Lieb ,James Mckay ,Rolf Adolfsson ,Dorret I Boomsma ,Stephan Ripke ,Jutta Kammerer-Ciernioch ,A J Forstner ,Josef Frank ,Martin Alda ,Stéphane Jamain ,Céline S Reinbold ,Margitta Borrmann-Hassenbach ,Michael John Owen ,Nick Bass ,Björn H Schott ,Ole A Andreassen ,Susan L Mcelroy ,Markus Schwarz ,Lisa Jones ,Andrea Pfennig ,Udo Dannlowski ,Peter R Schofield ,Martin Bohus ,Andreas Reif ,Hans J Grabe ,Marian L Hamshere ,Naomi R Wray ,Helmut Vedder ,Monika Budde ,Katrin Gade ,Anders D Børglum ,Ina Giegling ,Henriette Nørmølle Buttenschøn ,Anders Juréus ,José Guzmán-Parra ,Lynsey S Hall ,Liz Forty ,Nicholas G Martin ,Stefan Röepke ,James B Potash ,Huda Akil ,Enrico Domenici ,Roel A Ophoff ,Frank Bellivier ,Janice M Fullerton ,Douglas Blackwood ,Paul Brennan ,Toni‐Kim Clarke ,Stefan Herms ,Stefan Kloiber ,Sarah E Medland ,Urs Heilbronner ,Diana Schendel ,Jens Treutlein ,Sarah Kittel‐Schneider ,Gulja Babadjanova ,Yuri Milaneschi ,E K Green ,Q S Li ,Pablo Cervantes ,Fabio Rivas ,Martin Jungkunz ,Arian Mobascher ,Howard J Edenberg ,Christian Witt ,Ney Alliey‐Rodriguez ,Thomas G Schulze ,Gonneke Willemsen ,Joanna M Biernacka ,L Oruc ,Fabian Streit ,Martin Hautzinger ,Markus Leber ,Andrew M Mcintosh ,Tony Davis ,Ole Mors ,R Myers ,Christine Fraser ,Fermín Mayoral-Cleries ,Abdel Abdellaoui ,Michael Conlon O'donovan ,Christel M Middeldorp ,Martin Preisig ,Grant W Montgomery ,Eli A Stahl ,Sara A Paciga ,Swapnil Awasthi ,Gustavo Turecki ,Piotr M Czerski ,Amy Perry ,Nick Craddock ,Shashi Hitturlingappa ,Lydia Dietl ,Gunnar Morken ,Mikael Landén ,Christian Schmahl ,Hualin Simon Xi ,John S Strauss ,John I Nürnberger ,Grant Sinnamon ,Tracy Air ,Thomas W Mühleisen ,Srdjan Djurovic ,Marco P Boks ,André Tadić ,Bernhard T Baune ,Laura J Scott ,Mark A Frye ,Tiffany A Greenwood ,Sandra Van Der Auwera ,Loes Olde Loohuis ,John B Vincent ,Bertram Müller‐Myhsok ,Guy A Rouleau ,Cristiana Cruceanu ,Jolanta Lissowska ,Marcella Rietschel

doi:10.1038/tp.2017.115

Stephanie H Witt , Scott D Gordon + Show 151 more

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https://doi.org/10.1038/tp.2017.115

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Abstract

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Highlights

Borderline personality disorder (BOR; for the sake of readability, we have decided to use the rather unconventional abbreviation ‘BOR’ for Borderline Personality Disorder and the abbreviation ‘bipolar disorder (BIP)’ for Bipolar Disorder) is a complex neuropsychiatric disorder with a lifetime prevalence of around 3%.1 Untreated cases often have a chronic and severely debilitating clinical course.[1]
The results indicate that neither comorbidity with major depressive disorder (MDD) nor risk variants that are exclusive to MDD explain the genetic overlap between BOR and BIP, SCZ and MDD
In summary, the present study is the first genome-wide association study (GWAS) of patients diagnosed with BOR

Summary

Introduction

Borderline personality disorder (BOR; for the sake of readability, we have decided to use the rather unconventional abbreviation ‘BOR’ for Borderline Personality Disorder and the abbreviation ‘BIP’ for Bipolar Disorder) is a complex neuropsychiatric disorder with a lifetime prevalence of around 3%.1 Untreated cases often have a chronic and severely debilitating clinical course.[1]. Untreated cases often have a chronic and severely debilitating clinical course.[1] BOR affects up to. 20% of all psychiatric inpatients, and is associated with high health-care utilization. BOR represents a substantial socio-economic burden.[2,3]. Correspondence: Dr SH Witt, Central Institute of Mental Health, Department of Genetic Epidemiology in Psychiatry, University of Heidelberg, 68159 Mannheim, Germany. BOR is characterized by affective instability, emotional dysregulation and poor interpersonal functioning.[3] Suicide rates in BOR range between 6 and 8%, and up to 90% of patients engage in non-suicidal self-injurious behavior.[4] Other prototypical features include high-risk behaviors and impulsive aggression. Current theories view dysfunctions in emotion processing, social interaction and impulsivity as core psychological mechanisms of BOR.[5]

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