Genome-Wide Association Study Of Borderline Personality Disorder Reveals Genetic Overlap With Bipolar Disorder And Schizophrenia

Witt, Stephanie H.; Jungkunz, Martin; Streit, Fabian; Frank, Josef; Treutlein, Jens; Degenhardt, Franziska; Forstner, Andreas J.; Reinbold, Céline S.; Cichon, Sven; Nöthen, Markus M.; Awasthi, Swapnil; Ripke, Stephan; Mobascher, Arian; Rujescu, Dan; Lieb, Klaus; Röepke, Stefan; Schmahl, Christian; Bohus, Martin; Rietschel, Marcella

doi:10.1016/j.euroneuro.2016.09.524

Cited by 14 publications

(14 citation statements)

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“…In adolescent and adult samples, GWAS of externalizing PDs are still in their infancy, with only borderline and antisocial PDs being investigated to date, using relatively small samples. One molecular genetic study indicated that borderline PD is heritable 122 , but did not test for its genetic association with any other form of externalizing psychopathology. Current GWAS evidence indicates that antisocial behavior is heritable and significantly genetically correlated with CD and neuroticism, but not with schizophrenia, bipolar disorder or ADHD 121 .…”

Section: Validity Evidencementioning

confidence: 99%

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

et al. 2021

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The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical effort to address limitations of traditional mental disorder diagnoses. These include arbitrary boundaries between disorder and normality, disorder co‐occurrence in the modal case, heterogeneity of presentation within disorders, and instability of diagnosis within patients. This paper reviews the evidence on the validity and utility of the disinhibited externalizing and antagonistic externalizing spectra of HiTOP, which together constitute a broad externalizing superspectrum. These spectra are composed of elements subsumed within a variety of mental disorders described in recent DSM nosologies, including most notably substance use disorders and “Cluster B” personality disorders. The externalizing superspectrum ranges from normative levels of impulse control and self‐assertion, to maladaptive disinhibition and antagonism, to extensive polysubstance involvement and personality psychopathology. A rich literature supports the validity of the externalizing superspectrum, and the disinhibited and antagonistic spectra. This evidence encompasses common genetic influences, environmental risk factors, childhood antecedents, cognitive abnormalities, neural alterations, and treatment response. The structure of these validators mirrors the structure of the phenotypic externalizing superspectrum, with some correlates more specific to disinhibited or antagonistic spectra, and others relevant to the entire externalizing superspectrum, underlining the hierarchical structure of the domain. Compared with traditional diagnostic categories, the externalizing superspectrum conceptualization shows improved utility, reliability, explanatory capacity, and clinical applicability. The externalizing superspectrum is one aspect of the general approach to psychopathology offered by HiTOP and can make diagnostic classification more useful in both research and the clinic.

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Section: Validity Evidencementioning

confidence: 99%

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

et al. 2021

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“…Also implicated in calcium homeostasis in neuronal cells, as well as autophagy, and associated with AD and cancer [ 32 , 33 ] SERINC5 Serine incorporator 5 Involved in myelination. It adds serine into newly forming membrane lipids and is enriched in myelin in the brain [ 34 ] PLD1 Phospholipase D1 Involved in the regulation of cytoskeleton organization in neurons, in dendritic branching and spine regulation. Downregulation of PLD1 has been described to affect α-synuclein-triggered neurodegeneration in PD [ 35 ] NR4A3 Nuclear receptor subfamily 4, group A, member 3 Also known as neuron-derived orphan receptor-1.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic characterization of tissues from patients and subsequent pathway analyses reveal biological pathways that are implicated in spastic ataxia

et al. 2022

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Background Spastic ataxias (SAs) encompass a group of rare and severe neurodegenerative diseases, characterized by an overlap between ataxia and spastic paraplegia clinical features. They have been associated with pathogenic variants in a number of genes, including GBA2. This gene codes for the non-lysososomal β-glucosylceramidase, which is involved in sphingolipid metabolism through its catalytic role in the degradation of glucosylceramide. However, the mechanism by which GBA2 variants lead to the development of SA is still unclear. Methods In this work, we perform next-generation RNA-sequencing (RNA-seq), in an attempt to discover differentially expressed genes (DEGs) in lymphoblastoid, fibroblast cell lines and induced pluripotent stem cell-derived neurons derived from patients with SA, homozygous for the GBA2 c.1780G > C missense variant. We further exploit DEGs in pathway analyses in order to elucidate candidate molecular mechanisms that are implicated in the development of the GBA2 gene-associated SA. Results Our data reveal a total of 5217 genes with significantly altered expression between patient and control tested tissues. Furthermore, the most significant extracted pathways are presented and discussed for their possible role in the pathogenesis of the disease. Among them are the oxidative stress, neuroinflammation, sphingolipid signaling and metabolism, PI3K-Akt and MAPK signaling pathways. Conclusions Overall, our work examines for the first time the transcriptome profiles of GBA2-associated SA patients and suggests pathways and pathway synergies that could possibly have a role in SA pathogenesis. Lastly, it provides a list of DEGs and pathways that could be further validated towards the discovery of disease biomarkers.

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“…Studies should include genome wide analysis -GWAS [38,39], as multiple genes are thought to moderate the impact of early life stress on the development of BPD [40]. Epigenetic studies should also be utilised to help elucidate how child trauma influences gene-expression, thereby increasing vulnerability for BPD [36,40].…”

Section: Conclusion and Future Research Directionsmentioning

confidence: 99%

The aetiology of borderline personality disorder (BPD): contemporary theories and putative mechanisms

Winsper

2018

Current Opinion in Psychology

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This article presents an overview of current knowledge regarding the aetiology of Borderline Personality Disorder (BPD). It begins with a brief synopsis of early research and theory, and discusses how changing conceptualisations of BPD have impacted on our aetiological knowledge. Contemporary theories are described and presented within a developmental psychopathology framework. Deficient co-regulation and social communication in infancy are purported to underpin emotional dysregulation and social cognition deficits across development. These mechanisms are further potentiated by maladaptive social experiences in a series of positive feedback loops. Prospective research provides preliminary evidence for the reciprocal (or mediating) effects of maladaptive experiences and childhood dysregulation. Moving forward, cohort studies may incorporate neurobiological assessments to examine the biological systems underpinning phenotypic (e.g., impulsivity, disturbed relatedness) covariation.

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Genome-Wide Association Study Of Borderline Personality Disorder Reveals Genetic Overlap With Bipolar Disorder And Schizophrenia

Cited by 14 publications

References 0 publications

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

Transcriptomic characterization of tissues from patients and subsequent pathway analyses reveal biological pathways that are implicated in spastic ataxia

The aetiology of borderline personality disorder (BPD): contemporary theories and putative mechanisms

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