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. 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

S H Witt  1 F Streit  1 M Jungkunz  2   3 J Frank  1 S Awasthi  4 C S Reinbold  5 J Treutlein  1 F Degenhardt  6   7 A J Forstner  5   6   7   8 S Heilmann-Heimbach  6 L Dietl  9 C E Schwarze  10 D Schendel  1 J Strohmaier  1 A Abdellaoui  11 R Adolfsson  12 T M Air  13 H Akil  14 M Alda  15 N Alliey-Rodriguez  16 O A Andreassen  17   18 G Babadjanova  19 N J Bass  20 M Bauer  21 B T Baune  13 F Bellivier  22 S Bergen  23 A Bethell  24 J M Biernacka  25 D H R Blackwood  26 M P Boks  27 D I Boomsma  11 A D Børglum  28   29   30 M Borrmann-Hassenbach  31 P Brennan  32 M Budde  33   34 H N Buttenschøn  35 E M Byrne  36 P Cervantes  37 T-K Clarke  26 N Craddock  38 C Cruceanu  39 D Curtis  40   41 P M Czerski  42 U Dannlowski  43   44 T Davis  13 E J C de Geus  11 A Di Florio  38 S Djurovic  45   46 E Domenici  47 H J Edenberg  48   49 B Etain  50 S B Fischer  5 L Forty  38 C Fraser  38 M A Frye  51 J M Fullerton  52   53 K Gade  33   34 E S Gershon  16 I Giegling  54 S D Gordon  55 K Gordon-Smith  56 H J Grabe  57 E K Green  58 T A Greenwood  59 M Grigoroiu-Serbanescu  60 J Guzman-Parra  61 L S Hall  26   62 M Hamshere  38 J Hauser  42 M Hautzinger  63 U Heilbronner  34 S Herms  5   6   7 S Hitturlingappa  13 P Hoffmann  5   6   7 P Holmans  38 J-J Hottenga  11 S Jamain  50   64 I Jones  24 L A Jones  56 A Juréus  23 R S Kahn  65 J Kammerer-Ciernioch  66 G Kirov  38 S Kittel-Schneider  67 S Kloiber  68   69   70 S V Knott  56 M Kogevinas  71 M Landén  23   72 M Leber  73 M Leboyer  74 Q S Li  75 J Lissowska  76 S Lucae  70 N G Martin  55   77 F Mayoral-Cleries  61 S L McElroy  78 A M McIntosh  26   79 J D McKay  80 A McQuillin  20 S E Medland  55 C M Middeldorp  11 Y Milaneschi  81 P B Mitchell  82   83 G W Montgomery  84 G Morken  85   86 O Mors  87   88 T W Mühleisen  89   90 B Müller-Myhsok  39   91   92 R M Myers  93 C M Nievergelt  59 J I Nurnberger  94 M C O'Donovan  95 L M O Loohuis  96 R Ophoff  97 L Oruc  98 M J Owen  95 S A Paciga  99 B W J H Penninx  81 A Perry  56 A Pfennig  21 J B Potash  100 M Preisig  101 A Reif  67 F Rivas  61 G A Rouleau  102   103 P R Schofield  52   53 T G Schulze  1   33   34   104   105 M Schwarz  106 L Scott  107 G C B Sinnamon  108 E A Stahl  109   110 J Strauss  68 G Turecki  37 S Van der Auwera  57 H Vedder  106 J B Vincent  111 G Willemsen  11 C C Witt  112 N R Wray  36   113 H S Xi  114 Bipolar Disorders Working Group of the Psychiatric Genomics ConsortiumMajor Depressive Disorder Working Group of the Psychiatric Genomics ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumA Tadic  115   116 N Dahmen  116 B H Schott  4   117 S Cichon  6   89   90   118 M M Nöthen  6   7 S Ripke  4   119   120 A Mobascher  116 D Rujescu  54 K Lieb  116 S Roepke  9 C Schmahl  2 M Bohus  3 M Rietschel  1
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Free PMC article

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap With Bipolar Disorder, Major Depression and Schizophrenia

S H Witt et al. Transl Psychiatry. .
Free PMC article

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.

Conflict of interest statement

JIN Jr is an investigator for Assurex and a consultant for Janssen. AT has received consultancy fees from Janssen and Novartis. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Quantile–Quantile plot. Quantile–Quantile plot of the case–control analysis (998 cases; 1545 controls) showing expected and observed –log10 P-values. The shaded region indicates the 95% confidence interval of expected P-values under the null hypothesis.
Figure 2
Figure 2
Manhattan plot showing association results. Manhattan plot of the case–control analysis (998 cases; 1545 controls). For each single-nucleotide polymorphism (SNP), the chromosomal position is shown on the x axis, and the –log10 P-value on the y axis. The red line indicates genome-wide significance (P<5 × 10−8) and the blue line indicates suggestive evidence for association (P<1 × 10−5).
Figure 3
Figure 3
Polygenic risk score analysis. The proportion of variance explained in case–control status (y axis; Nagelkerke’s R2) by the PRS for BIP, SCZ and MDD is depicted for the different P-value cutoffs used in the calculation of the PRS. Principal components were included in the models to control for population stratification. 1*, P<0.05; 2*, P<0.001; 3*, P<1 × 10−4; 4*, P<1 × 10−6; 5*, P<1 × 10−8; 6*, P<1 × 10−10; 7*, P<1 × 10−12. BIP, bipolar disorder; MDD, major depressive disorder; NS, nonsignificant; PRS, polygenic risk score; SCZ, schizophrenia.
Figure 4
Figure 4
Polygenic risk score analysis in subgroups. Mean z-standardized PRS and standard error (s.e.) for BIP, SCZ and MDD are shown in the control group, all cases, and in cases with and without comorbid MDD. PRS with a P-value threshold of P=0.05 were selected for this comparison and principal components were included in the models to control for population stratification. The numbers at the top of each bar indicate the significance of the difference in the respective PRS in comparison with the control group. 1*, P<0.05; 2*, P<0.001; 3*, P<1 × 10−4; 4*, P<1 × 10−6; 5*, P<1 × 10−8; 6*, P<1 × 10−10; 7*, P<1 × 10−12. BIP, bipolar disorder; BOR, borderline personality disorder; MDD, major depressive disorder; NS, nonsignificant; PRS, polygenic risk score; SCZ, schizophrenia.

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