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

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

Authors/Editors: Witt SH, Streit F, Jungkunz M, Frank J, Awasthi S, Reinbold CS, Treutlein J, Degenhardt F, Forstner AJ, Heilmann-Heimbach S, Dietl L, Schwarze CE, Schendel D, Strohmaier J, Abdellaoui A, Adolfsson R, Air TM, Akil H, Alda M, Alliey-Rodriguez N, Andreassen OA, Babadjanova G, Bass NJ, Bauer M, Baune BT, Bellivier F, Bergen S, Bethell A, Biernacka JM, Blackwood DHR, Boks MP, Boomsma DI, Børglum AD, Borrmann-Hassenbach M, Brennan P, Budde M, Buttenschøn HN, Byrne EM, Cervantes P, Clarke TK, Craddock N, Cruceanu C, Curtis D, Czerski PM, Dannlowski U, Davis T, de Geus EJC, Di Florio A, Djurovic S, Domenici E, Edenberg HJ, Etain B, Fischer SB, Forty L, Fraser C, Frye MA, Fullerton JM, Gade K, Gershon ES, Giegling I, Gordon SD, Gordon-Smith K, Grabe HJ, Green EK, Greenwood TA, Grigoroiu-Serbanescu M, Guzman-Parra J, Hall LS, Hamshere M, Hauser J, Hautzinger M, Heilbronner U, Herms S, Hitturlingappa S, Hoffmann P, Holmans P, Hottenga JJ, Jamain S, Jones I, Jones LA, Juréus A, Kahn RS, Kammerer-Ciernioch J, Kirov G, Kittel-Schneider S, Kloiber S, Knott SV, Kogevinas M, Landén M, Leber M, Leboyer M, Li QS, Lissowska J, Lucae S, Martin NG, Mayoral-Cleries F, McElroy SL, McIntosh AM, McKay JD, McQuillin A, Medland SE, Middeldorp CM, Milaneschi Y, Mitchell PB, Montgomery GW, Morken G, Mors O, Mühleisen TW, Müller-Myhsok B, Myers RM, Nievergelt CM, Nurnberger JI, O'Donovan MC, Loohuis LMO, Ophoff R, Oruc L, Owen MJ, Paciga SA, Penninx BWJH, Perry A, Pfennig A, Potash JB, Preisig M, Reif A, Rivas F, Rouleau GA, Schofield PR, Schulze TG, Schwarz M, Scott L, Sinnamon GCB, Stahl EA, Strauss J, Turecki G, Van der Auwera S, Vedder H, Vincent JB, Willemsen G, Witt CC, Wray NR, Xi HS; 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 A, Dahmen N, Schott BH, Cichon S, Nöthen MM, Ripke S, Mobascher A, Rujescu D, Lieb K, Roepke S, Schmahl C, Bohus M, Rietschel M.
Publication Date: 2017

2017_06_witt

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.

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