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

2017; Springer Nature; Volume: 7; Issue: 6 Linguagem: Inglês

10.1038/tp.2017.115

2158-3188

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

Bipolar Disorder and Treatment

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, P FDR =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 ( r g =0.28 [ P =2.99 × 10 −3 ]), SCZ ( r g =0.34 [ P =4.37 × 10 −5 ]) and MDD ( r g =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.