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

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.

Evolutionarily developed connections compromised in schizophrenia

“…Like schizophrenia, these disorders involve widespread changes in brain connectivity and evolutionary pressure on network organization may similarly have played a role in the neurobiological architecture of these disorders. Indeed, the notion that potential nonspecificity of evolutionary changes in cortical connectivity may play a role in a wide range of mental health disorders is supported by GWAS studies showing significant overlap in genetic risk between schizophrenia, bipolar disorder and major depression (39).…”

Autism and Williams syndrome: dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood

“…PKP4 encodes a protein involved in cellular adhesion, motility and division, as well as neurite outgrowth (Keil et al, 2013). The gene has been implicated in the sexual dimorphism observed in ASD , but it has been associated as well to bipolar disorder, major depression, and schizophrenia (Witt et al, 2017). PVALB, which encodes parvalbumin, is expressed in GABAergic interneurons in many brain regions of interest for the ASD and WS pathogenesis, including the thalamus, the cortex, and the basal ganglia (Schwaller et al, 2002).…”

The Storytelling Brain: How Neuroscience Stories Help Bridge the Gap between Research and Society

“…It is also becoming clear that specific mental disorders are not well categorized. There is some evidence that various mental illnesses overlap at the level of behaviors as well as their neurobiological substrates (Witt et al, 2017). For example, there is current scientific consensus that the PFC is the main site of disruption in people with schizophrenia (Selemon and Zecevic, 2015), although its network of connections with other parts of the brain may be abnormal, too.…”