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

Witt, S.H., Streit, F., Landen, M., Leber, M., Leboyer, M., Kammerer-Ciernioch, J., Kirov, G., Kittel-Schneider, S., Kloiber, S., Knott, S.V., Kogevinas, M., Kahn, R.S., Jamain, S., Jones, I., Jones, L.A., Jureus, A., Hottenga, J-J., Holmans, P., Hautzinger, M., Heilbronner, U., Herms, S., Hitturlingappa, S., Hoffmann, P., Hauser, J., Davis, T., de Geus, E.J.C., Di Florio, A., Djurovic, S., Domenici, E., Edenberg, H.J., Etain, B., Fischer, S.B., Forty, L., Fraser, C., Frye, M.A., Fullerton, J.M., Gade, K., Gershon, E.S., Giegling, I., Gordon, S.D., Gordon-Smith, K., Grabe, H.J., Green, E.K., Greenwood, T.A., Grigoroiu-Serbanescu, M., Guzman-Parra, J., Hall, L.S., Hamshere, M., Czerski, P.M., Dannlowski, U., Cruceanu, C., Curtis, D., Craddock, N., Clarke, T-K., Cervantes, P., Byrne, E.M., Buttenschon, H.N., Budde, M., Brennan, P., Borrmann-Hassenbach, M., Borglum, A.D., Boomsma, D.I., Boks, M.P., Blackwood, D.H.R., Biernacka, J.M., Bethell, A., Bergen, S., Bellivier, F., Baune, B.T., Bauer, M., Bass, N.J., Babadjanova, G., Andreassen, O.A., Alliey-Rodriguez, N., Alda, M., Akil, H., Air, T.M., Adolfsson, R., Abdellaoui, A., Strohmaier, J., Schendel, D., Schwarze, C.E., Dietl, L., Heilmann-Heimbach, S., Forstner, A.J., Degenhardt, F., Treutlein, J., Reinbold, C.S., Frank, J., Awasthi, S., Jungkunz, M., Li, Q.S., Lissowska, J., Lucae, S., Martin, N.G., Mayoral-Cleries, F., McElroy, S.L., McIntosh, A.M., McKay, J.D., McQuillin, A., Medland, S.E., Witt, C.C., Middeldorp, C.M., Milaneschi, Y., Mitchell, P.B., Montgomery, G.W., Morken, G., Mors, O., Muehleisen, T.W., Mueller-Myhsok, B., Myers, R.M., Nievergelt, C.M., Nurnberger, J.I., O'Donovan, M.C., Loohuis, L.M.O., Ophoff, R., Oruc, L., Owen, M.J., Paciga, S.A., Penninx, B.W.J.H., Perry, A., Pfennig, A., Potash, J.B., Preisig, M., Reif, A., Rivas, F., Rouleau, G.A., Schofield, P.R., Schulze, T.G., Schwarz, M., Scott, L., Sinnamon, G.C.B., Stahl, E.A., Strauss, J., Turecki, G., Van der Auwera, S., Vedder, H., Vincent, J.B., Willemsen, G., Wray, N.R., Xi, H.S., Tadic, A., Dahmen, N., Schott, B.H., Cichon, S., Noethen, M.M., Ripke, S., Mobascher, A., Rujescu, D., Lieb, K., Roepke, S., Schmahl, C., Bohus, M., and Rietschel, M. (2017) Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia. Translational Psychiatry, 7.

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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 x 10(-7)) and PKP4 (P = 8.67 x 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 (r(g) = 0.28 [P = 2.99 x 10(-3)]), SCZ (r(g) = 0.34 [P = 4.37 x 10(-5)]) and MDD (r(g) = 0.57 [P = 1.04 x 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.

Item ID: 50352
Item Type: Article (Research - C1)
ISSN: 2158-3188
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Funders: Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI), GlaxoSmithKline, Faculty of Biology and Medicine of Lausanne, Switzerland, Swiss National Science Foundation (SNSF), German Federal Ministry of Education and Research (BMBF), German Research Foundation (DFG)
Projects and Grants: UEFISCDI 89/2012, SNSF 3200B0-105993, SNSF 3200B0-118308, SNSF 33CSCO-122661, SNSF 33CSCO-139468, SNSF 33CSCO-148401, BMBF 01ZX1314A, BMBF 01ZX1314G, DFG FOR2017, DFG RI908/11-1, DFG WI3429/3-1, DFG NO246/01-1, DFG DA1151/5-1, DFG KFO 256 BO 1487/12-1, DFG SFB 779 TP A08
Date Deposited: 20 Sep 2017 08:13
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1117 Public Health and Health Services > 111714 Mental Health @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110311 Medical Genetics (excl Cancer Genetics) @ 50%
SEO Codes: 92 HEALTH > 9204 Public Health (excl. Specific Population Health) > 920410 Mental Health @ 50%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 20%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 30%
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