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

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.

Prenatal adversity: a risk factor in borderline personality disorder?

BACKGROUND: Patients with borderline personality disorder (BPD) show a high prevalence of early adversity, such as childhood trauma. It has also been reported that prenatal adverse conditions, such as prenatal maternal stress, drug taking, tobacco smoking or medical complications, may be associated with an increased risk of mental disorders in the offspring. Prenatal adversity is investigated here for the first time as a potential risk factor in the diagnosis of BPD. Method A total of 100 patients with a DSM-IV diagnosis of BPD and 100 matched healthy controls underwent semi-structured interviews about the course of pregnancy, maternal stressors, birth complications and childhood trauma. Further information was obtained from the participants' mothers and from prenatal medical records. RESULTS: Borderline patients were significantly more often exposed to adverse intrauterine conditions, such as prenatal tobacco exposure (p=0.004), medical complications (p=0.008), prenatal maternal traumatic stress (p=0.015), familial conflicts (p=0.004), low social support (p=0.004) and partnership problems during pregnancy (p=0.014). Logistic regression analyses revealed that the reported prenatal risk factors accounted for 25.7% of the variance in BPD. Prenatal tobacco exposure [odds ratio (OR) 3.37, 95% confidence interval (CI) 1.49-7.65, p=0.004] and medical complications (OR 2.87, 95% CI 1.29-6.38, p=0.010) emerged as important predictors. After controlling for childhood adversity and parental socio-economic status (SES), prenatal risk factors predicted relevant borderline subdomains, such as impulsivity, affective instability, identity disturbance, dissociation and severity of borderline symptoms. CONCLUSIONS: This study provides evidence of an association between prenatal adversity and the diagnosis of BPD. Our findings suggest that prenatal adversity may constitute a potential risk factor in the pathogenesis of BPD.