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Transl Psychiatry. 2017 Jun 20;7(6):e1155. doi: 10.1038/tp.2017.115.

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

Witt SH1, Streit F1, Jungkunz M2,3, Frank J1, Awasthi S4, Reinbold CS5, Treutlein J1, Degenhardt F6,7, Forstner AJ5,6,7,8, Heilmann-Heimbach S6, Dietl L9, Schwarze CE10, Schendel D1, Strohmaier J1, Abdellaoui A11, Adolfsson R12, Air TM13, Akil H14, Alda M15, Alliey-Rodriguez N16, Andreassen OA17,18, Babadjanova G19, Bass NJ20, Bauer M21, Baune BT13, Bellivier F22, Bergen S23, Bethell A24, Biernacka JM25, Blackwood DHR26, Boks MP27, Boomsma DI11, Børglum AD28,29,30, Borrmann-Hassenbach M31, Brennan P32, Budde M33,34, Buttenschøn HN35, Byrne EM36, Cervantes P37, Clarke TK26, Craddock N38, Cruceanu C39, Curtis D40,41, Czerski PM42, Dannlowski U43,44, Davis T13, de Geus EJC11, Di Florio A38, Djurovic S45,46, Domenici E47, Edenberg HJ48,49, Etain B50, Fischer SB5, Forty L38, Fraser C38, Frye MA51, Fullerton JM52,53, Gade K33,34, Gershon ES16, Giegling I54, Gordon SD55, Gordon-Smith K56, Grabe HJ57, Green EK58, Greenwood TA59, Grigoroiu-Serbanescu M60, Guzman-Parra J61, Hall LS26,62, Hamshere M38, Hauser J42, Hautzinger M63, Heilbronner U34, Herms S5,6,7, Hitturlingappa S13, Hoffmann P5,6,7, Holmans P38, Hottenga JJ11, Jamain S50,64, Jones I24, Jones LA56, Juréus A23, Kahn RS65, Kammerer-Ciernioch J66, Kirov G38, Kittel-Schneider S67, Kloiber S68,69,70, Knott SV56, Kogevinas M71, Landén M23,72, Leber M73, Leboyer M74, Li QS75, Lissowska J76, Lucae S70, Martin NG55,77, Mayoral-Cleries F61, McElroy SL78, McIntosh AM26,79, McKay JD80, McQuillin A20, Medland SE55, Middeldorp CM11, Milaneschi Y81, Mitchell PB82,83, Montgomery GW84, Morken G85,86, Mors O87,88, Mühleisen TW89,90, Müller-Myhsok B39,91,92, Myers RM93, Nievergelt CM59, Nurnberger JI94, O'Donovan MC95, Loohuis LMO96, Ophoff R97, Oruc L98, Owen MJ95, Paciga SA99, Penninx BWJH81, Perry A56, Pfennig A21, Potash JB100, Preisig M101, Reif A67, Rivas F61, Rouleau GA102,103, Schofield PR52,53, Schulze TG1,33,34,104,105, Schwarz M106, Scott L107, Sinnamon GCB108, Stahl EA109,110, Strauss J68, Turecki G37, Van der Auwera S57, Vedder H106, Vincent JB111, Willemsen G11, Witt CC112, Wray NR36,113, Xi HS114; Bipolar Disorders Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Tadic A115,116, Dahmen N116, Schott BH4,117, Cichon S6,89,90,118, Nöthen MM6,7, Ripke S4,119,120, Mobascher A116, Rujescu D54, Lieb K116, Roepke S9, Schmahl C2, Bohus M3, Rietschel M1.

Author information

1
Central Institute of Mental Health, Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
2
Central Institute of Mental Health, Clinic of Psychosomatic and Psychotherapeutic Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3
Central Institute of Mental Health, Institute for Psychiatric and Psychosomatic Psychotherapy (IPPP)/Psychosomatic Medicine and Psychotherapy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
4
Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
5
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
6
Institute of Human Genetics, University of Bonn, Bonn, Germany.
7
Life and Brain Center, Department of Genomics, University of Bonn, Bonn, Germany.
8
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
9
Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
10
Department of Clinical Psychology and Psychotherapy, University of Heidelberg, Heidelberg, Germany.
11
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
12
Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden.
13
Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
14
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
15
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
16
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
17
Division Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
18
NORMENT, University of Oslo, Oslo, Norway.
19
Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
20
Division of Psychiatry, University College London, London, UK.
21
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Dresden, Germany.
22
Inserm, U1144, AP-HP, GH Saint-Louis, Département de Psychiatrie et de Médecine Addictologique, Paris, France.
23
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
24
National Center for Mental Health, Cardiff University, Cardiff, UK.
25
Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
26
Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
27
Urain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
28
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
29
iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
30
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
31
Medical and Quality Assurance, Clinics of Upper Bavaria, Munich, Germany.
32
Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
33
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Goettingen, Germany.
34
Medical Center of the University of Munich, Campus Innenstadt, Institute of Psychiatric Phenomics and Genomics (IPPG), Munich, Germany.
35
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
36
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
37
Department of Psychiatry, McGill University, Montreal, QC, Canada.
38
Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
39
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
40
Centre for Psychiatry, Queen Mary University of London, London, UK.
41
UCL Genetics Institute, University College London, London, UK.
42
Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
43
Department of Psychiatry, University of Marburg, Marburg, Germany.
44
Department of Psychiatry, University of Münste, Münster, Germany.
45
Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo, Norway.
46
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
47
Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy.
48
Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA.
49
Indiana University School of Medicine, Department of Medical and Molecular Genetics, Indianapolis, IN, USA.
50
Faculté de Médecine, Université Paris Est, Créteil, France.
51
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
52
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
53
Neuroscience Research Australia, Sydney, NSW, Australia.
54
Department of Psychiatry, University of Halle, Halle, Germany.
55
Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
56
Department of Psychological Medicine, University of Worcester, Worcester, UK.
57
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
58
School of Biomedical and Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
59
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
60
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
61
Mental Health Department, Biomedicine Institute, University Regional Hospital, Málaga, Spain.
62
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
63
Department of Psychology, Eberhard Karls Universität Tübingen, Tubingen, Germany.
64
Inserm U955, Psychiatrie Translationnelle, Créteil, France.
65
University Medical Center Utrecht, Division of Neuroscience, Department of Psychiatry, Utrecht, The Netherlands.
66
Center of Psychiatry Weinsberg, Weinsberg, Germany.
67
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
68
Centre for Addiction and Mental Health, Toronto, ON, Canada.
69
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
70
Max Planck Institute of Psychiatry, Munich, Germany.
71
Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
72
Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
73
Clinic for Psychiatry and Psychotherapy, University Hospital Cologne, Cologne, Germany.
74
Inserm U955, Translational Psychiatry Laboratory, AP-HP, DHU PePSY, Department of Psychiatry, Université Paris Est, Créteil, France.
75
Janssen Research and Development, LLC, Neuroscience Therapeutic Area, Titusville, NJ, USA.
76
M. Sklodowska-Curie Cancer Center and Institute of Oncology, Cancer Epidemiology and Prevention, Warsaw, Poland.
77
School of Psychology, The University of Queensland, Brisbane, QLD, Australia.
78
Lindner Center of HOPE, Research Institute, Mason, OH, USA.
79
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
80
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
81
VU University Medical Center and GGZ inGeest, Department of Psychiatry, Amsterdam, The Netherlands.
82
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
83
Black Dog Institute, Sydney, NSW, Australia.
84
Institute for Molecular Biology, University of Queensland, Brisbane, QLD, Australia.
85
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
86
Department of Psychiatry, St Olavs University Hospital, Trondheim, Norway.
87
Risskov, Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark.
88
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
89
Research Center Juelich, Institute of Neuroscience and Medicine (INM-1), Juelich, Germany.
90
Division of Medical Genetics, University of Basel, Basel, Switzerland.
91
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
92
University of Liverpool, Liverpool, UK.
93
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
94
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
95
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
96
Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA, USA.
97
University Medical Center Utrecht, Division of Brain Research, Utrecht, The Netherlands.
98
Psychiatry Clinic, Clinical Center University of Sarajevo, Sarajevo, Bosnia-Herzegovina.
99
Pfizer Global Research and Development, Human Genetics and Computational Biomedicine, Groton, CT, USA.
100
Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
101
Department of Psychiatry, Psychiatric University Hospital of Lausanne, Lausanne, Switzerland.
102
Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada.
103
Montreal Neurological Institute and Hospital, Montreal, QC, Canada.
104
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
105
NIMH Division of Intramural Research Programs, Human Genetics Branch, Bethesda, MD, USA.
106
Psychiatric Center Nordbaden, Wiesloch, Germany.
107
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
108
School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.
109
Broad Institute of MIT and Harvard, Medical and Population Genetics, Cambridge, MA, USA.
110
Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
111
Centre for Addiction and Mental Health, Molecular Neuropsychiatry and Development Laboratory, Toronto, ON, Canada.
112
Department of Anaesthesiology and Operative Intensive Care, University Hospital Mannheim, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
113
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
114
Pfizer Global Research and Development, Computational Sciences Center of Emphasis, Cambridge, MA, USA.
115
AGAPLESION Elisabethenstift gGmbh, Department of Psychiatry, Psychosomatics and Psychotherapy, Darmstadt, Germany.
116
University Medical Center, Department of Psychiatry and Psychotherapy, Mainz, Germany.
117
Leibniz Institute for Neurobiology, Magdeburg, Germany.
118
Department of Biomedicine, University of Basel, Basel, Switzerland.
119
Stanley Center for Psychiatric Research and Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
120
Analytic and Translational Genetics Unit, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.

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.

PMID:
28632202
PMCID:
PMC5537640
DOI:
10.1038/tp.2017.115
[Indexed for MEDLINE]
Free PMC Article

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