The present study is the first to use molecular genetic data to investigate shared genetic factors between diagnosed BPD and the Big Five personality traits, showing a genetic correlation of BPD with the trait Neuroticism and a suggestive correlation with Openness. These results provide biological evidence that partially supports the concept that associates variants of normal personality traits and the presence of BPD. Specifically, it supports the description of BPD as high levels of neuroticism and openness, although the original proposal includes also low levels of agreeableness and conscientiousness (Lynam & Widiger, 2001).
The observed genetic correlation of BPD and Neuroticism is in line with findings from twin and family studies, showing a positive genetic overlap of Neuroticism and Borderline Personality Features (Distel et al. 2009), a continuous measure of borderline personality assessed with the Personality Assessment Inventory–Borderline Features scale (PAI-BOR) which can be used in the general population (Morey 1991) or BPD DSM-IV Criterion counts (Czajkowski et al. 2018). A polygenic risk score summarizing the genetic risk burden for Borderline Personality Features (Lubke et al. 2014) was associated with Neuroticism (smallest p=5.43*10−7) in a target sample of >100,000 subjects from the general population (Gale et al. 2016), supporting a genetic relation between both phenotypes.
Phenotypic studies implicate that Neuroticism increases risk for most psychiatric disorders (Caspi et al. 2014; Lahey 2009; Ormel et al. 2013). It is likely that a genetic disposition to Neuroticism also contributes to genetic correlations between many psychiatric disorders (Anttila et al. 2018) and the observed comorbidities (Grant et al. 2008). With respect to depression, strong genetic correlations of Neuroticism with both depressive symptoms in the general population as well as with clinical MDD have been observed (Lo et al. 2017; Wray et al. 2018). As a broad genetic risk factor, Neuroticism might link BPD to other (comorbid) psychiatric conditions as well as other personality disorders (Krueger 2005). Supporting this, a twin study showed that the finding of a genetic association between Borderline Personality Features and substance use disorders, is attributable to variation in personality factors, especially Neuroticism (Few et al. 2014).
Neuroticism comprises facets which are characteristic clinical features of BPD personality, such as emotional lability, anxiousness, angry hostility, depressiveness, and vulnerability (e.g. Trull and Widiger 2013). In the present study, BPD showed similar correlations with both tested Neuroticism clusters, with slightly a higher correlation for “Depressed Affect”. In the item-based analysis, all 12 items showed a positive correlation with BPD, with nominal significance for 10, and significance after Bonferroni correction for four of the 12 items. The results indicate that a rather broad range of aspects of Neuroticism contributes to BPD, similar to depression and anxiety, and distinct from disorders such as schizophrenia, anorexia nervosa or attention deficit hyperactivity disorder, which show primarily association with one of the two clusters (Nagel, Watanabe, et al. 2018). Notably, the most strongly correlated item was “mood swings” which has previously been used as a measure of mood instability (Ward et al. 2020), a core symptom of BPD (Koenigsberg 2010). “Mood swings” has shown extensive genetic overlap with a range of mental disorders, with the strongest positive correlations being reported for depression, anxiety, ADHD and PTSD (Ward et al. 2020; Hindley et al. 2021). Future research should further investigate how single items, and specific clusters of these features contribute to different psychiatric disorders (Mõttus et al. 2020).
Less is known about the genetic correlation of Openness with BPD and other psychiatric disorders, although high level of Openness to feelings and to actions have been proposed to characterize BPD (Lynam and Widiger 2001). In twin studies, Openness for Experience showed a moderate genetic correlation with DSM-IV Criterion counts for BPD (r=.24) (Czajkowski et al. 2018) but no evidence for a genetic correlation with Borderline Personality Features (Distel et al. 2009). Using a molecular genetic approach, we observed a nominally significant genetic correlation (rg=.24). These disparities may be attributable to the different instruments used in the studies, or to the fact that the present results are based on a sample of patients fulfilling the diagnosis of BPD (Witt et al. 2017), and not on normal variation observed in Borderline Personality Features in unaffected subjects. It is unclear however, if this might entail differences in statistical power, or in the underlying genetic architecture.
While Openness is generally considered a beneficial personality trait, in high levels and in combination with other traits it might be disadvantageous and increase the risk for certain psychiatric disorders (Trull 2012). The present results suggest that increased Openness and BPD might be influenced by overlapping genetic factors. Openness has for example been associated with aspects of risk-taking including substance use (Booth-Kewley and Vickers Jr 1994; Nicholson et al. 2005), and increased risk-taking is a characteristic feature of BPD which contributes strongly to the impairment experienced by affected patients and their relatives. Furthermore, both Openness (Larøi et al. 2005) and BPD (Slotema et al. 2012) are associated with hallucinations; shared genetic variants associated might underlie these associations. Openness has been shown to be genetically associated to other psychiatric disorders such as BD and SCZ (Lo et al. 2017), and BPD and SCZ share a sizable fraction of genetic risk factors (Witt et al. 2017). Still, compared to Neuroticism, Openness has been less strongly linked with BPD, and while all facets of Neuroticism are related to the BPD phenotype, only Openness to feelings and actions do (Trull 2012). In regard to the association of BPD with other Big Five traits, there are inconsistencies with previous studies: the results of twin studies (Czajkowski et al. 2018; Distel et al. 2009) and clinical observations (Trull 2012) indicate a negative association of Borderline Personality with Agreeableness and Conscientiousness, whereas we observe genetic correlations close to zero.
There are some limitations to the study: First, while BPD showed genetic correlations with two of the Big Five, the effects and the statistical significance of the results are limited in the case of Openness, where the association did not survive correction for multiple testing. Larger samples are needed to confirm and expand the observed associations: despite being the largest available samples for the phenotypes, the samples for the Big Five and especially, the BPD GWAS are limited in size. Increased sample sizes will be able to provide more reliable estimates of the underlying genetic risk variants. The sample of BPD is drastically smaller compared to those of other psychiatric disorders such as MDD (Howard et al. 2019), BD (Mullins et al. 2021) and SCZ (Ripke et al. 2020). Clinicians and researchers in the field of BPD should work together to facilitate the generation of larger BPD case-control samples for genetic studies. Second, we assessed genetic correlations to assess shared genetic overlap. However, more complex genetic overlap, with a mix of agonistic and antagonistic shared effects can remain undetected by this approach, as it has been shown e.g. for bipolar disorder and cognition (Smeland et al. 2020). Third, different personality inventories were used in the different studies to assess the personality traits. However, high genetic correlations were reported for the personality traits between the samples (Lo et al. 2017; Nagel, Jansen, et al. 2018; all rg > .83). Fourth, the available samples were all from European ancestry, which limits the transferability of the results to other populations. Fourth, the GWAS by Lo et al. (Lo et al. 2017) investigated sum scores of personality domains, but did not investigate the respective facets. While our cluster and item-based analyses for Neuroticism indicate specific contributions of personality clusters/facets, no item-based data was available to us for the other Big Five traits. Future genetic studies of BPD and the Big Five and should assess the Big Five and their facets in more detail.
The present study shows the applicability of molecular genetic approaches to investigating the extent to which common genetic factors underlie personality traits and BPD. Future research should extend the present analysis, by leveraging data from large and well characterized samples. Besides detailed analyses of the underlying personality facets, future research should investigate functional domains involved in BPD and the Big Five, as formulated in the Research Domain Criteria (RDoC) approach (Insel 2014). The present study investigated genetic associations of BPD with the Big Five. It should be noted that environmental factors such as early or recent trauma and chronic stress, which are highly important contributors to BPD (Bohus et al. in press; Lieb et al. 2004; Zimmerman and Choi-Kain 2009), influence the development of personality not only in early age, but also throughout the entire lifetime (Briley and Tucker-Drob 2017). Identifying and assessing the relevant aspects of environmental exposure suspected to modify biological pathways is a major challenge, especially when the pathways are thought to link normal variation in personality traits to personality disorders. Future studies integrating environmental aspects in as much detail and as reliably as possible will be able to further address the interplay of environmental and genetic factors in the analyses (e.g. Colodro-Conde et al. 2018; Coleman et al. 2020).
In summary, the present study gives the first molecular genetic insight into the shared genetic factors underlying BPD and normal variation in the Big Five personality traits and supports the relationship of BPD and Neuroticism. Future studies may extend this approach to the specific underlying genetic variants and other psychiatric conditions, thereby helping to further elucidate the relationship between psychopathology and normal variability of human personality.