Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in families? A population-based study of 2 million Swedes

Abstract

Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979–2001, and identified their diagnoses during 1997–2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6–20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0–42.2; full siblings, aOR = 2.8, 95% CI = 2.6–3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2–1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3–1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

Full text

Molecular Psychiatry (2021) 26:341–349
https://doi.org/10.1038/s41380-018-0248-5
ARTICLE
Do borderline personality disorder and attention-deficit/
hyperactivity disorder co-aggregate in families? A population-based
study of 2 million Swedes
Ralf Kuja-Halkola 1●Kristina Lind Juto1●Charlotte Skoglund2●Christian Rück 2●David Mataix-Cols2●
Ana Pérez-Vigil2●Johan Larsson2●Clara Hellner2●Niklas Långström1,3 ●Predrag Petrovic4●Paul Lichtenstein 1●
Henrik Larsson1,5
Received: 7 February 2018 / Revised: 6 August 2018 / Accepted: 8 August 2018 / Published online: 15 October 2018
© The Author(s) 2018. This article is published with open access
Abstract
Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline
personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of
clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we
included individuals born in Sweden 1979–2001, and identified their diagnoses during 1997–2013; in total, 2,113,902
individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient
care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4
(95% confidence interval [95% CI] =18.6–20.4) of also having a BPD diagnosis, compared to individuals not
diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR =11.2, 95%
CI =3.0–42.2; full siblings, aOR =2.8, 95% CI =2.6–3.1; maternal half-siblings, aOR =1.4, 95% CI =1.2–1.7; paternal
half-siblings, aOR =1.5, 95% CI =1.3–1.7). Cousins also had an increased risk. The strength of the association between
ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among
both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests
shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of
increased risks for BPD in individuals with ADHD and their relatives, and vice versa.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a com-
mon neurodevelopmental disorder [1], with a general
population prevalence of 5–10% in childhood [2] and about
2–5% in adulthood [3]. Comorbid disorders associated with
ADHD include neurodevelopmental (e.g., autism spectrum
disorders), externalizing (e.g., substance use disorders), and
internalizing disorders (e.g., depression and anxiety dis-
orders) [4–6]. Borderline personality disorder (BPD) is a
common personality disorder, with onset in adolescence,
and prevalence in the adult general population of about
1–4% [7–9]. BPD is characterized by emotional dysregu-
lation [10] leading to severely impaired interpersonal
functioning, extensive use of health care, and a high risk of
suicide [8]. Although it is increasingly recognized that
emotional dysregulation is important also in ADHD,
population-based data on the co-occurrence of ADHD and
BPD within individuals and co-aggregation in families are
Preliminary results were presented at the Behavior Genetics Annual
meeting in San Diego, USA, 2015.
*Ralf Kuja-Halkola
ralf.kuja-halkola@ki.se
1Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet, Stockholm, Sweden
2Centre for Psychiatry Research, Department of Clinical
Neuroscience, Karolinska Institutet, & Stockholm Health Care
Services, Stockholm County Council, Norra Stationsgatan 69,
SE-113 64 Stockholm, Sweden
3Department of Neuroscience, Uppsala University,
Uppsala, Sweden
4Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden
5School of Medical Sciences, Örebro University, Örebro, Sweden
Electronic supplementary material The online version of this article
(https://doi.org/10.1038/s41380-018-0248-5) contains supplementary
material, which is available to authorized users.
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still lacking [11]. A better understanding of this comorbidity
is important. First, it may contribute to the understanding of
shared mechanisms underlying both ADHD and BPD [10].
Second, if these disorders share underlying mechanisms, it
would suggest that treatment strategies for one disorder may
be effective for the other [10].
The association between ADHD and BPD has been
addressed in epidemiological studies, suggesting that the
disorders often co-occur in the same individuals [11], an
association first highlighted in a study of self-reported
childhood ADHD symptoms in BPD cases, compared to
controls, by Fossati et al. in 2002 [12]. More recently, a
Swedish study found that the prevalence of BPD in indi-
viduals with ADHD was 37.0% [13], and in a German
sample of adult women with BPD, 41.5% were screen-
positive for childhood history of ADHD of which 16.1%
had ADHD symptoms that persisted into adulthood [14]. A
study based on self-reports from approximately 34,000 US
individuals found that 33.7% with ADHD also self-reported
BPD as compared to 5.2% in the general population [15].
However, as these prior results were mainly based on either
small clinical samples or self-reported data, it remains
unclear if the co-occurrence of clinically diagnosed ADHD
and BPD is present at the population level.
Family and twin studies suggest that susceptibility to
ADHD is largely genetic in origin [16–19]. A number of
studies have demonstrated genetic overlaps of ADHD with
neurodevelopmental, e.g. [5,20], externalizing, e.g. [21],
and internalizing disorders, e.g. [22].but little is known
about the extent to which the genetic risk factors of ADHD
are also shared with BPD. Only one twin study has inves-
tigated the genetic and environmental contributions to the
association between ADHD- and BPD-traits. It showed that
half of the association between ADHD and BPD was
explained by genetic factors, while the remaining part of the
association was explained by environmental factors unique
to the individual [23]. Whether these findings generalize to
individuals with clinically diagnosed ADHD and BPD and
to non-twin samples remains to be investigated.
The main objective of the current study was to estimate
the co-occurrence and familial co-aggregation between
clinically diagnosed ADHD and BPD in a total population
cohort.
Materials and methods
Study population
We linked Swedish registers through the unique personal
identification number given to each Swedish citizen. The
Medical Birth Register [24] provided sex and birth date; we
included everyone born between 1 January 1979 and
31 December 2001 (2,319,694 individuals). We excluded
stillbirths, congenital malformations, and deaths during
infancy (108,079). Using the Cause of Death Register [25],
we excluded individuals who died before their 12th birthday
(6283). Via the Total Population Register [26] we excluded
individuals who emigrated before their 12th birthday
(72,337). Age 12 represents the latest age of first pre-
sentation of ADHD symptoms according to DSM-5.
Finally, using the Multi-Generation Register [27], we linked
individuals to their biological parents, and excluded indi-
viduals who did not have both parents known (19,093),
yielding a sample of 2,113,902 individuals. The Multi-
Generation Register and the Twin Register [28] allowed us
to identify relatives: monozygotic twins (sharing essentially
100% of alleles), dizygotic twins (sharing on average 50%
of co-segregating alleles), full siblings (50% of co-
segregating alleles), maternal half-siblings (25%), paternal
half-siblings (25%); cousins whose parents were full sib-
lings (12.5%); cousins whose parents were maternal- and
paternal half-siblings (6.25%).
The study was approved by the Regional Ethical
Review Board in Stockholm (Dnr 2013/862–31/5); since
it was a registry study no individual was contacted,
and informed consent was waived. The validation sub-
study was approved by the Swedish Central Ethics Board
(Dnr Ö 27-2012).
Study variables
We linked the data to the Swedish National Patient Register
[29] (NPR) and Prescribed Drug Register [30] (PDR). The
NPR comprises diagnoses from inpatient health care, and
from outpatient visits to specialist care from 2001 and
onwards [29]; we used International Classification of Dis-
eases 10th revision [31] (ICD-10) diagnoses from 1 January
1997 (when ICD-10 was introduced in Sweden) to 31
December 2013. We used data from PDR on all dispensed
medications from 1 June 2005 to 31 December 2014.
We identified individuals with ADHD from the NPR
(ICD-10 code F90; Hyperkinetic Disorder) and/or from the
PDR via prescriptions of ADHD medications (methylphe-
nidate, amphetamine, dexamphetamine, lisdexamfetamine,
or atomoxetine). Details supporting the validity of this
definition are available in previous publications, including
the validity of using ADHD medications as proxy for
ADHD diagnosis [32,33].
We identified individuals with BPD from the NPR
(ICD-10 code F60.3; Emotionally Unstable Personality
Disorder, the diagnosis code used in Swedish version of
ICD-10 to correspond to DSM-IV-TR Borderline Person-
ality Disorder) [34]. As the validity of the BPD diagnosis in
the NPR had not been previously investigated, we per-
formed a separate validation study, following a previously
342 R. Kuja-Halkola et al.
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described methodology [35]. Briefly, we requested 100
randomly selected medical records for men and women with
a BPD diagnosis in the NPR. Two clinically experienced,
board-certified, adult psychiatrists independently examined
the records employing DSM-IV-TR (very similar to the
ICD-10 research criteria) when assessing diagnosis in the
records. Evidence of diagnosis was considered to be present
if (a) at least five of the nine criteria in BPD were endorsed
in the record or whether a diagnostic instrument (SCID-II)
had been employed to establish a diagnosis of BPD, or (b)
the clinicians held an expert opinion that a BPD diagnosis
was the most likely explanation for the patients symptoms
given the information available. We received 82 of the
requested records, and 70 had sufficient information to
assess diagnosis. The agreement for endorsed diagnosis
between examiners was good (93%; 95% confidence
interval [95% CI], 84–98) as was the inter-rater reliability
for number of endorsed criteria (Cohens kappa [36], 0.82;
95% CI, 0.74–0.90). Disagreements on endorsing diagnosis
(5 records) were solved by using the least favorable rater
(i.e., if one rated as “not BPD”then her rating had pre-
cedence). According to (a) 44 diagnoses could be con-
firmed, with the addition of (b) this number increased to 57
records, corresponding to positive predictive values (PPV)
of 63% (95% CI =50–74) and 81% (95% CI =70–90).
Sex, birth year, and birth order are collectively referred to
as the covariates below—included since they are potential
confounders, associated with both ADHD and BPD. Birth
year was included as a covariate to adjust for the secular
changes affecting diagnostic practices through the follow-
up period; for instance, incidence of ADHD diagnoses has
seen a sharp increase. Birth order was included because the
position among siblings may affect the likelihood of getting
diagnoses.
Statistical analyses
We estimated associations using logistic regression, thus
viewing ADHD and BPD as binary variables. The choice of
logistic regression, even though age at diagnosis is acces-
sible to us, reflects that we do not believe the date of
diagnosis accurately captures the date of disease onset.
Additionally this means that analyses of temporal order of
diagnoses could be misleading. To estimate appropriate
associations we instead rely on a carefully selected cohort
with reasonable follow-up, adjustment for birth year, and
sensitivity analyses.
Co-occurrence within individuals
We analyzed the within-individual association between
ADHD (exposure) and BPD (outcome) to obtain crude and
covariate-adjusted odds ratios (OR and aOR). Note though
that the choice of which of diagnoses to view as exposure
and outcome is arbitrary in the current design. We calcu-
lated proportions of BPD among those with and without
ADHD in the total cohort and separately by sex (crudely
and standardized over covariates) [37], and the corre-
sponding proportions of ADHD in BPD.
Co-aggregation within relatives
We estimated the risk of BPD (outcome) in individuals
according to their relatives’ADHD (exposure): crude and
adjusted for covariates, including covariates for the relative.
Similarly as in the within-individual analyses the choice of
exposure and outcome is arbitrary. Comparing estimates
across relatives informs about the role of genetic and/or
environmental risk factors shared by the disorders. If the
association between monozygotic twins is weaker than the
within-individual association, then factors not shared by
family members are likely to influence the co-occurrence. If
the association between full siblings is weaker than between
monozygotic twins, and the association between maternal
half-siblings is weaker than between full siblings, genetic
factors are likely to influence the association. Maternal half-
siblings have similar intra-uterine environment, and usually
grow up in similar environments since children pre-
dominantly stay with the mother following parental
separation [38,39]. Hence, a stronger association in
maternal than paternal half-siblings suggest shared
environment.
Further, we calculated ORs in the full sibling subsample
stratified by sex combinations, and calculated proportions
with BPD diagnosis. We calculated similar proportions
using ADHD as outcome and BPD as exposure.
All analyses were performed in R, adjusting the precision
of estimates for dependencies within family clusters using
cluster-robust sandwich estimators, employing the packages
drgee [40] and stdReg [37].
Sensitivity analyses
Alternative diagnostic definitions
The main cohort covered many birth years to provide rea-
sonable power for both the within individual and the rela-
tive analyses, which introduced a potential risk of bias due
to both left truncation (i.e., we started following some birth
cohorts later in life) and right censoring (i.e., individuals
were not followed until death). To investigate if results were
influenced by this we identified a sub-cohort where BPD
was defined as present if an individual was eligible to get a
diagnosis through high-risk age period from age 18 until at
least age 23, taking migration and deaths into account, and
was diagnosed with BPD at any time (including before age
Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in. . . 343
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18 and after age 23). If the individual did not have an
uninterrupted period with possibility to get a diagnosis
between ages 18 and 23—due to end of follow-up, not
being alive, or not living in Sweden—we defined BPD as
missing; else we defined it as “no BPD”.Wedefined
ADHD correspondingly, with safeguarded observation from
age 7 until age 12. Using these definitions, we investigated
the robustness of associations.
Test of familial factors
Between full siblings, we adjusted analyses for ADHD
occurrence in the outcome individual, yielding estimates not
interpretable as familial risks since the adjustment intro-
duces bias. However, this analysis helps determine whether
a shared familial cause (e.g., genetic) for an association
likely exists, regardless of if one disease causes the other
directly. If the association remains despite such adjustment,
this supports the notion of a liability for both
disorders shared by relatives (see, e.g., [41] for further
explanation).
Results
Co-occurrence within individuals
During follow-up 82,593 (3.9%) individuals were diag-
nosed with ADHD, while 9544 (0.5%) were diagnosed with
BPD (Table 1). Males were more frequently diagnosed with
ADHD, while BPD diagnoses were more common among
females. Among individuals with an ADHD diagnosis,
3.6% had also been diagnosed with BPD (2952 out of
82,593; Table 2), with a higher proportion in females
(8.0%) compared to males (1.0%; Table 2). Among indi-
viduals with a BPD diagnosis, 30.9% had also been diag-
nosed with ADHD (2952 out of 9544), with a higher
proportion in males (40.1%) compared to females (29.6%;
Table 2). Calculating proportions standardized over cov-
ariates suggest that the increase was not due to a skewed
age- and/or sex distribution (Supplemental Table 1a and c).
Having an ADHD diagnosis increased the odds of a BPD
diagnosis 11.4 times (95% CI =10.9–11.9; Table 3), and
even more so after adjustment for covariates (aOR =19.4,
95% CI =18.6–20.4; Table 3). In Supplemental Table 2
separate adjustment for each covariate are presented; both
for within individual and relatives analyses adjustment for
birth year had the largest impact on the estimates. The
association was stronger in women compared to men (aOR
=19.1 vs. 21.8; p=0.047; Table 4), but this difference did
not remain statistically significant in sensitivity analysis
with observation ensured in high-risk periods (p=0.720;
Supplemental Table 3).
Co-aggregation within relatives
Having a relative with an ADHD diagnosis increased the
odds of a BPD diagnosis (Table 3). The aOR for mono-
zygotic twins (11.2, 95% CI =3.0–42.2) was lower than
within individuals, which indicate that factors not shared by
Table 1 Descriptive information Total sample
N(column percent)
ADHD
N(row percent)
BPD
N(row percent)
ADHD and BPD
N(row percent)
Sample 2,113,902 (100%) 82,593 (3.9%) 9544 (0.5%) 2952 (0.1%)
Covariates
Sex
Female 1,031,987 (48.8%) 30,571 (3.0%) 8307 (0.8%) 2456 (0.2%)
Male 1,081,915 (51.2%) 52,022 (4.8%) 1237 (0.1%) 496 (<0.1%)
Birth years
1979–1984 505,457 (23.9%) 10,763 (2.1%) 3761 (0.7%) 1091 (0.2%)
1985–1989 483,733 (22.9%) 13,989 (2.9%) 3601 (0.7%) 1102 (0.2%)
1990–1994 543,344 (25.7%) 24,095 (4.4%) 2079 (0.4%) 711 (0.1%)
1995–2001 581,368 (27.5%) 33,746 (5.8%) 103 (<0.1%) 48 (<0.1%)
Birth order by mother
1 874,369 (41.4%) 35,204 (4.0%) 4179 (0.5%) 1316 (0.2%)
2 772,164 (36.5%) 28,406 (3.7%) 3143 (0.4%) 974 (0.1%)
3 332,840 (15.7%) 12,512 (3.8%) 1505 (0.5%) 422 (0.1%)
4 94,430 (4.5%) 4380 (4.6%) 504 (0.5%) 159 (0.2%)
5 26,228 (1.2%) 1398 (5.3%) 140 (0.5%) 57 (0.2%)
>5 13,873 (0.7%) 693 (5.0%) 73 (0.5%) 24 (0.2%)
344 R. Kuja-Halkola et al.
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family members are likely to influence the co-occurrence.
The aOR for dizygotic twins was 1.0, with a wide CI (95%
CI =0.1–7.3)—reflecting the low power for these relatives.
Among full siblings, the aOR was 2.8 (95% CI =2.6–3.1),
significantly lower compared to monozygotic twins (p=
0.041), suggesting that at least part of the association
between BPD and ADHD is explained by genetic factors.
The aORs were lower in both maternal (1.4, 95% CI =1.2–
1.7) and paternal half-siblings (1.5, 95% CI =1.3–1.7)
compared to full siblings (both p< 0.001), again supporting
genetic contributions to the association. Further, maternal
and paternal half-sibling estimates did not differ sig-
nificantly from each other (p=0.671), indicating that
shared environmental effects have little or no impact on the
association. Cousins whose parents were full siblings had
an increased risk of having a diagnosis of BPD, aOR, 1.5
(95% CI =1.4–1.6), while cousins whose parents were half-
siblings had even lower aOR.
Table 2 Proportion of BPD and ADHD in individuals with the other diagnosis, and in individuals whose relatives have the other diagnosis
No. of individuals Proportion of BPD—outcome
Percent (95% CI)
Proportion of ADHD—outcome
Percent (95% CI)
No ADHD ADHD No BPD BPD
Within individual
Both sexesa2,113,902 0.3% (0.3–0.3) 3.6% (3.4–3.7) 3.8% (3.8–3.8) 30.9% (30.0–31.9)
Females onlya1,031,987 0.6% (0.6–0.6) 8.0% (7.7–8.3) 2.7% (2.7–2.8) 29.6% (28.6–30.5)
Males onlya1,081,915 0.1% (0.1–0.1) 1.0% (0.9–1.0) 4.8% (4.7–4.8) 40.1% (37.4–42.8)
Full siblings No. of pairsb
Both sexes 2,211,396 0.4% (0.4–0.4) 0.9% (0.9–1.0) 3.4% (3.4–3.4) 7.8% (7.2–8.4)
Female outcome female exposure 523,464 0.7% (0.7–0.7) 1.9% (1.6–2.1) 2.6% (2.5–2.6) 6.6% (5.8–7.4)
Female outcome male exposure 552,516 0.7% (0.7–0.8) 1.5% (1.3–1.7) 2.6% (2.6–2.7) 8.6% (6.2–11.0)
Male outcome female exposure 552,516 0.1% (0.1–0.1) 0.3% (0.2–0.4) 4.2% (4.2–4.3) 8.4% (7.6–9.3)
Male outcome male exposure 582,900 0.1% (0.1–0.1) 0.2% (0.2–0.3) 4.1% (4.0–4.2) 10.6% (7.9–13.3)
Half-siblings Pairsb
Both maternal and paternal 663,566 0.9% (0.8–0.9) 1.3% (1.2–1.3) 7.7% (7.6–7.8) 10.6% (9.9–11.4)
Notes: 95% CI 95% confidence intervals
aCluster-robust standard errors based on mothers as clusters
bNumber of unique ways of combining pairs, i.e., a pair may be included twice, first with A as outcome person and B as exposure person, then with
B as outcome person and A as exposure person
Table 3 Odds ratio of a BPD
diagnosis when having an
ADHD diagnosis oneself, or a
relative diagnosed with ADHD
No. of individuals Crude odds ratio
(95% CI)
Adjusted odds ratioa
(95% CI)
Within individualb2,113,902 11.4 (10.9–11.9) 19.4 (18.6–20.4)
Relatives No. of pairsc
Monozygotic twins 9130 5.0 (1.5–16.9) 11.2 (3.0–42.2)
Dizygotic twins 17,350 0.6 (0.1–4.7) 1.0 (0.1–7.3)
Full siblings 2,211,396 2.4 (2.2–2.6) 2.8 (2.6–3.1)
Maternal half-siblings 332,486 1.4 (1.2–1.6) 1.4 (1.2–1.7)
Paternal half-siblings 331,080 1.5 (1.3–1.6) 1.5 (1.3–1.7)
Cousins parents full siblings 6,456,848 1.4 (1.3–1.5) 1.5 (1.4–1.6)
Cousins parents maternal half-siblings 472,212 1.2 (1.0–1.4) 1.3 (1.1–1.5)
Cousins parents paternal half-siblings 466,836 1.2 (1.0–1.4) 1.2 (1.0–1.4)
Notes: 95% CI 95% confidence intervals
aAdjusted for sex, sex of relative, birth year, birth year of relative, birth order, and birth order of relative,
wherever applicable
bCluster-robust standard errors based on mothers as clusters
cNumber of unique ways of combining pairs, i.e., a pair may be included twice, first with A as outcome
person and B as exposure person, then with B as outcome person and A as exposure person
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If etiological sex differences were present (e.g., partly
different genetic factors being responsible for the overlap
between the disorders in males and females) the increased
risk for BPD would be expected to differ depending on sex.
That is, a same-sex sibling with ADHD should increase the
risk for BPD more compared to having an opposite-sex
sibling with ADHD. Further, it has been suggested that
females’ADHD diagnoses possibly represent a stronger
genetic load compared to males [42]. If this genetic load
was also associated with BPD, siblings of females with
ADHD should have an increased risk of BPD compared to
siblings of males with ADHD. In full siblings, females
having a sister with ADHD had an increased risk of having
a BPD diagnosis compared to females having a brother with
ADHD (aOR =2.9 vs. 2.5; Table 4). Males with a sister
diagnosed with ADHD also exhibited increased risk com-
pared to males with a brother with ADHD (aOR =3.9 vs
3.6; Table 4). However, neither of these differences were
statistically significant (p=0.087 in females and p=0.683
in males; Table 4). Thus, etiological sex differences were
not robustly supported.
Sensitivity analyses
Alternative diagnostic definitions
Analyses safeguarding follow-up during high-risk periods
in ADHD and BPD revealed similar patterns of proportions
of diagnoses, although with slightly higher percentages,
5.1% for ADHD and 0.7% for BPD (Supplemental
Table 4). Analyses suggested ORs largely similar to those
found in the main analysis, both within individuals and
relatives (Supplemental Table 3). Corresponding results for
proportion with diagnoses also followed the same pattern as
seen with the original diagnostic definitions (Supplemental
Table 1b and d).
Test of familial factors
Analyses of full siblings with additional adjustment of
ADHD in the outcome person found OR significantly
higher than 1 (aOR =1.4, 95% CI =1.2–1.5). Altogether,
findings support that familial factors are partly responsible
for the observed co-aggregation within relatives, and not an
artifact of one disorder causing the other within individuals.
Discussion
This is the largest study of ADHD and BPD co-occurrence,
in a total population of over 2.1 million individuals, and the
only one exploring familial co-aggregation of clinically
diagnosed ADHD and BPD. We found that individuals with
a diagnosis of ADHD had a 19.4 times higher odds of BPD
diagnosis than individuals not diagnosed with ADHD.
Furthering a previous twin study on the relation between
ADHD- and BPD-like traits [23], the pattern of familial co-
aggregation of ADHD and BPD across different types of
relatives indicated that genetic factors play a role in ADHD
and BPD co-occurrence. Our results should contribute to
improved understanding of the mechanisms underlying both
ADHD and BPD [10].
Emotional dysregulation has since long been hypothesized
to underlie BPD, but also suggested to be an important aspect
of ADHD [43–45]. This is in line with our results indicating
that the shared genetic origin of ADHD and BPD may reflect
a load of emotional dysregulation processes involved in both
disorders, that the processes underlying the disorders are
separate but correlated, or a combination thereof [10].
Although genetic factors were implied, the estimated
associations between siblings compared to within indivi-
duals indicated that not all of the association was explained
by these factors. Similarly to a previous study [23], our
Table 4 Odds ratio of a BPD
diagnosis when having an
ADHD diagnosis oneself, or a
full sibling diagnosed with
ADHD. Sex-specific analyses
No. of individuals Crude odds ratio
(95% CI)
Adjusted odds ratioa
(95% CI)
p-Valueb
Within femalesc1,031,987 14.9 (14.2–15.6) 19.1 (18.2–20.1) 0.047
Within malesc1,081,915 13.4 (11.9–15.0) 21.8 (19.3–24.5)
Full siblings No. of pairsd
Female outcome female exposure 523,464 2.7 (2.3–3.1) 2.9 (2.6–3.4) 0.087
Female outcome male exposure 552,516 2.1 (1.9–2.3) 2.5 (2.3–2.8)
Male outcome female exposure 552,516 3.5 (2.6–4.7) 3.9 (2.9–5.4) 0.683
Male outcome male exposure 582,900 2.8 (2.1–3.7) 3.6 (2.7–4.8)
Notes: 95% CI 95% confidence intervals
aAdjusted for birth year, birth year of relative, birth order, and birth order of relative, where applicable
bFor pairwise comparison of adjusted estimates
cCluster-robust standard errors based on mothers as clusters
dNumber of unique ways of combining pairs, i.e., a pair may be included twice, first with A as outcome
person and B as exposure person, then with B as outcome person and A as exposure person
346 R. Kuja-Halkola et al.
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results indicate that individually unique factors, including a
potential direct (phenotypic/causal) effect of ADHD diag-
nosis on the probability of getting a BPD diagnosis, are
likely to explain parts of the association.
We found that BPD was more common among females,
while ADHD was more so among males. In contrast, the data
supported no, or only minor, differences in etiological factors
responsible for the observed associations between ADHD and
BPD in males and females. This may suggest that differences
in the co-occurrence rates between males and females are
probably explained by other factors, such as detection bias or
diagnostic traditions—supportedbylackevidenceofsex
differences in prevalence when assessed by face-to-face
interviews of adults in the US [46].
Limitations of this study include under-detection; the
observed diagnoses are likely underestimations of the true
proportion of individuals with symptom levels and impair-
ments corresponding to diagnoses if assessed by healthcare
professionals. Some individuals may have a diagnosis
registered in sources not accessible by us, e.g. outpatient
care prior to 2001, or just do not seek help. Under-detection
would be likely to bias estimates towards null. Since ADHD
and BPD are likely to suffer from different detection biases
—including different likelihood of detection depending on
during which ages the individuals were followed up in
available registries—we performed sensitivity analyses in a
subsample with better coverage in high-risk periods for both
diagnoses; no major differences in results appeared (Sup-
plemental Table 3). Another limitation, likely to bias esti-
mates upwards, is correlated detection bias; individuals with
a diagnosis, or their relatives, will be in closer contact with
health care and therefore have a higher probability of
receiving another diagnosis compared to individuals with
similar symptom- and impairment levels without other
diagnoses. Another potential source of bias is misdiagnosis,
where, for instance, BPD may be misdiagnosed as ADHD
by a clinician and later more correctly diagnosed as BPD,
thus introducing a spurious association between the dis-
orders. Such diagnostic issues are plausible because of
overlaps in the diagnostic symptom criteria between ADHD
and BPD [11]. Another limitation is that the register diag-
noses used are set by clinicians without enforced standar-
dized procedures in place. This may increase the
heterogeneity of symptom profiles sharing the same diag-
nosis and are likely to result in less specificity of diagnoses.
However, it also represents a more naturalistic result of the
relation between diagnoses given in the clinical environ-
ment. For our ADHD-definition we did not include ICD-10
diagnosis F98.8—“Other specified behavioral and emo-
tional disorders with onset usually occurring in childhood
and adolescence”—which include “Attention-deficit dis-
order without hyperactivity”(ADD). This because of
inability to discern this important sub-diagnosis from other
sub-diagnoses (i.e., excessive masturbation, nail-biting,
nose-picking, and thumb-sucking), as well as it being
questionable if this sub-diagnosis is consistently used for
ADD in concurrent clinical practice. Thus, we may be
missing to identify some individuals with ADD, while
avoiding incorrectly identifying individuals without ADHD
problems as having ADHD diagnosis. However, in our data,
only 739 individuals had F98.8 without ADHD according
to our definition, and a post-hoc analysis including F98.8
did not change our results (Supplemental Table 5). We did
not follow individuals throughout their lives, thus they were
at risk of receiving a diagnosis outside the follow-up
period. However, when enforcing follow-up through high-
risk periods for ADHD and BPD, associations remained
robust.
Important strengths of the current study are its population-
based cohort, sample size, and clinically diagnosed ADHD
and BPD. Although both ADHD and BPD are likely to
include heterogeneous presentations, the diagnoses are likely
to capture the DSM-IV-criteria accurately—the validation of
the ICD-10 BPD codes showed adequate agreement (93%)
and acceptable precision (PPV =81%). A further strength is
the use of population registers, where data are gathered pro-
spectively and primarily for administrative purposes, and,
importantly, totally independently from the current study.
ADHD and BPD co-occur in individuals, and co-
aggregate in relatives—reflecting both shared genetic risk
factors and individually unique risk factors. Although
ADHD is more common in males and BPD in females, the
strength of the individual and familial associations between
the disorders is similar across sexes, indicating that etiologic
sex differences are unlikely. Clinicians need to be aware of
increased risk for BPD in individuals with a diagnosis of
ADHD, as well as in their relatives, and vice versa.
Disclaimer
The funders had no role in the design and conduct of the
study; collection, management, analysis, and interpretation
of the data; preparation, review, or approval of the manu-
script; and decision to submit the manuscript for publication.
Acknowledgements This research was supported by the Swedish
Prison and Probation Service (Kuja-Halkola and Lind Juto).
Compliance with ethical standards
Conflict of interest HL has served as a speaker for Eli Lilly and Shire
and has received a research grant from Shire. PL has served as a
speaker for Medicine, all outside the submitted work. The remaining
authors declare that they have no conflict of interest.
Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in. . . 347
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