This is the first total-population study of familial aggregation and heritability of clinically diagnosed BPD. Confirming previous studies, relatives of individuals with a diagnosis of BPD had a higher risk of receiving a BPD-diagnosis than those without familial vulnerability. For example, there was a 4.7 times increased risk for full siblings. Heritability of clinically diagnosed BPD was estimated at 46% (95% CI = 39–53), consistent with previous studies demonstrating the heritability of dimensional BPD-traits in general population twin samples. The best fitting model indicated little or no role for shared familial environmental factors. Thus, the pattern of familial aggregation of BPD across different types of relatives indicates that genetic factors play a significant role in the risk of developing BPD, and explain the familial clustering of the disorder.

Previous heritability estimates vary widely [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37] and our results represent a substantial improvement in precision, based on our sample size and the number of BPD-diagnosed individuals, as reflected in the narrow confidence intervals for the heritability estimates. Furthermore, our findings indicate that close family members of individuals represent an important high-risk group for developing BPD; and that this is due to genetic, and not environmental, influences. This has important implications. Firstly, clinicians need to be aware of the elevated risks for BPD in relatives of BPD-patients. Secondly, although thus far no single nucleotide polymorphism (genetic variant) have been identified that reach genome-wide significance [53, 54], future molecular genetic studies may, given sufficient sample sizes, identify some of the genetic risk factors that confer risk for BPD.

The results also estimate a 54% contribution of non-shared, individually unique, environmental factors. Shared environment did not influence the statistical goodness of fit, suggesting that shared familial environmental factors, such as socioeconomics, are unlikely to contribute substantially to the etiological underpinnings of BPD. Traumatic life events, such as sexual or physical abuse and parental divorce or illness, are more frequently reported by individuals with BPD compared to healthy controls or patients with other personality disorders [8, 55,56,57,58]. Although no given environmental risk factor has yet to be clearly identified as causative, our findings suggest that these may reflect unique environmental risks to individuals within a family or might act via gene-by-environment interactions. Further, these environmental associations could also reflect gene-environment correlations, additionally complicating the identification of specific environmental risks. The identification of unique environmental risk factors and gene-by-environment interactions for BPD should be regarded a research priority, as these are potentially preventable or modifiable via early interventions.

In line with previous research, the pattern of comorbid disorders showed that comorbidity is a hallmark of BPD. One potential cause for high comorbidity rates is genetic overlap since recent research findings indicate high genetic overlap across many psychiatric disorders and a general genetic propensity [59, 60]. Thus, our results are likely to partly reflect non-specific genetic effects that acts across mental health disorders. Here we did not adjust our analyses for any comorbid conditions since adjustment would most likely influence our results in a non-interpretable way.

On a mechanistic level, it has been suggested that several underlying neural and cognitive processes involved in emotional regulation are dysfunctional in BPD [1]. The present study suggests that that these underlying deficits are largely genetically predetermined. Such regulatory processes are thought to involve widely distributed large-scale neural networks, including specific prefrontal and anterior cingulate regions, networks involved in emotional processing, basal ganglia circuits, and neuromodulatory systems such as dopamine and noradrenaline systems [1, 2].

Since we had categorical yes/no measure of BPD, we necessarily treated it as a categorical variable in analyses, rather than having continuous measures or separate symptoms. Concurrent research has found that many psychiatric diagnoses are representable as the extreme end of a continuous trait [61], although no study specifically addressing this in BPD has been performed. Further, recent research supports a close association between categorical BPD-criteria (i.e., BPD-symptoms) and corresponding trait dimensions of personality disorders [62, 63]. Thus, BPD-diagnoses, as used in current study, likely represent the same underlying psychopathological construct as previous work using symptoms and/or dimensional measures of BPD-traits.

This study has several important strengths including utilizing Swedish nationwide register linkages. Previous studies are often limited by small sample sizes [7,8,9,10, 13,14,15,16, 19, 34, 36] the use of BPD-traits rather than diagnosis [7, 9, 10, 19,20,21,22,23,24, 28, 29, 31,32,33, 35,36,37, 64], and self-rating questionnaires [16, 19, 21,22,23,24,25,26,27,28, 30] rather than clinical diagnoses, exposing them to risks of low statistical power, selection- and recall bias. This register-based population cohort provided large sample-size, well-identified biological relatives, extensive follow-up time, and clinical diagnoses. Furthermore, data was gathered consecutively and independently from the current study. Moreover, previous studies investigating etiological underpinnings of BPD are predominantly based on twins. This study uses multiple types of relatives, and quantitative genetic analysis was performed in a sibling sample.

Our results need to be interpreted in light of some limitations. First, we most likely underestimate the true proportion of individuals with symptom levels and impairments corresponding to BPD-diagnosis (i.e., more cases would be identified if everyone in the cohort was assessed for BPD). Second, it is possible that we are missing male individuals with BPD in our population sample as the female to male ratio in our study is 5.5:1, whereas a more even sex ratio has been reported in a US community sample assessed by interview [4]. Results remained stable in women, but we did not have sufficient power to perform the quantitative genetic analysis in men; thus, generalization of our findings to men with BPD should be made with caution. Third, the BPD-diagnosis is based on fulfilling at least five out of nine symptom criteria leading to clinically significant distress or functional impairment in important life areas, and thus a substantial heterogeneity of symptom profiles exists. Although heterogeneity may hamper specificity of the diagnosis, our previous medical chart validation study demonstrated the correspondence of the register-based diagnoses with the DSM-IV criteria [45]. Further, identified individuals with a diagnosis of BPD in our population comprise those in contact with the health care system, thus representing the “real world” cases, and are most likely a representative sample of individuals suffering from functional impairment related to BPD-symptoms. Fourth, our methods will not detect individuals diagnosed in outpatient care prior to 2001. Importantly, however, under-detection of BPD is likely to bias the estimates towards the null. Fifth, relatives to individuals with a BPD-diagnosis may be in closer contact with health care and consequently be more likely to receive a diagnosis, thus inflating the estimates due to detection bias. Sixth, BPD is reported to be most prevalent in adolescence, and its prevalence decreases significantly towards the age of 24 [19]. We detected different incidence rates of BPD across different calendar periods with an increased propensity of assigning BPD-diagnosis at earlier ages, a phenomenon that may indicate changes in diagnostic practice. The extended twin/family design makes it less sensitive to trends in diagnostic practice; if time or local trends are present they are likely to apply to the population in a similar way. Lastly, our follow-up periods started later in older cohorts. The results might be affected by left truncation, missing earlier onset BPD. However, BPD is often described as a disorder of “stable instability” [6, 23, 55, 65, 66], resulting in repeated interactions with health care, increasing the likelihood of being identified as carrying a diagnosis in the current study.

In conclusion, BPD aggregates in families and the heritability was estimated at 46%, with the remaining variance explained by non-shared environmental factors. This finding is important for further expanding our understanding of BPD. The time is ripe for identification of genetic variants associated with BPD through large scale genome-wide studies, for identification of environmental risk factors, and of how these correlate or interact to increase the risk of BPD.