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


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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.
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Molecular Psychiatry (2021) 26:341349
Do borderline personality disorder and attention-decit/
hyperactivity disorder co-aggregate in families? A population-based
study of 2 million Swedes
Ralf Kuja-Halkola 1Kristina Lind Juto1Charlotte Skoglund2Christian Rück 2David Mataix-Cols2
Ana Pérez-Vigil2Johan Larsson2Clara Hellner2Niklas Långström1,3 Predrag Petrovic4Paul 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
Large-scale family studies on the co-occurrence of attention-decit/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 19792001, and identied their diagnoses during 19972013; 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% condence interval [95% CI] =18.620.4) 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 =3.042.2; full siblings, aOR =2.8, 95% CI =2.63.1; maternal half-siblings, aOR =1.4, 95% CI =1.21.7; paternal
half-siblings, aOR =1.5, 95% CI =1.31.7). 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.
Attention-decit/hyperactivity disorder (ADHD) is a com-
mon neurodevelopmental disorder [1], with a general
population prevalence of 510% in childhood [2] and about
25% 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) [46]. Borderline personality disorder (BPD) is a
common personality disorder, with onset in adolescence,
and prevalence in the adult general population of about
14% [79]. 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
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
( 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 rst 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 [1619]. 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 ndings 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
Materials and methods
Study population
We linked Swedish registers through the unique personal
identication 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 rst 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 2013/86231/5); 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 Classication 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 identied 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
denition are available in previous publications, including
the validity of using ADHD medications as proxy for
ADHD diagnosis [32,33].
We identied 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]. Briey, we requested 100
randomly selected medical records for men and women with
a BPD diagnosis in the NPR. Two clinically experienced,
board-certied, 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 ve 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 sufcient information to
assess diagnosis. The agreement for endorsed diagnosis
between examiners was good (93%; 95% condence
interval [95% CI], 8498) as was the inter-rater reliability
for number of endorsed criteria (Cohens kappa [36], 0.82;
95% CI, 0.740.90). Disagreements on endorsing diagnosis
(5 records) were solved by using the least favorable rater
(i.e., if one rated as not BPDthen her rating had pre-
cedence). According to (a) 44 diagnoses could be con-
rmed, with the addition of (b) this number increased to 57
records, corresponding to positive predictive values (PPV)
of 63% (95% CI =5074) and 81% (95% CI =7090).
Sex, birth year, and birth order are collectively referred to
as the covariates belowincluded 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
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, reects 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 relativesADHD (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 inuence 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 inuence 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
Further, we calculated ORs in the full sibling subsample
stratied 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 denitions
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
inuenced by this we identied a sub-cohort where BPD
was dened 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-decit/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 23due to end of follow-up, not
being alive, or not living in Swedenwe dened BPD as
missing; else we dened it as no BPD.Wedened
ADHD correspondingly, with safeguarded observation from
age 7 until age 12. Using these denitions, 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
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 =10.911.9; Table 3), and
even more so after adjustment for covariates (aOR =19.4,
95% CI =18.620.4; 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 signicant 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 =3.042.2) was lower than
within individuals, which indicate that factors not shared by
Table 1 Descriptive information Total sample
N(column percent)
N(row percent)
N(row percent)
N(row percent)
Sample 2,113,902 (100%) 82,593 (3.9%) 9544 (0.5%) 2952 (0.1%)
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
19791984 505,457 (23.9%) 10,763 (2.1%) 3761 (0.7%) 1091 (0.2%)
19851989 483,733 (22.9%) 13,989 (2.9%) 3601 (0.7%) 1102 (0.2%)
19901994 543,344 (25.7%) 24,095 (4.4%) 2079 (0.4%) 711 (0.1%)
19952001 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 inuence the co-occurrence.
The aOR for dizygotic twins was 1.0, with a wide CI (95%
CI =0.17.3)reecting the low power for these relatives.
Among full siblings, the aOR was 2.8 (95% CI =2.63.1),
signicantly 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 =1.31.7)
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-
nicantly 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 =1.41.6), 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 BPDoutcome
Percent (95% CI)
Proportion of ADHDoutcome
Percent (95% CI)
Within individual
Both sexesa2,113,902 0.3% (0.30.3) 3.6% (3.43.7) 3.8% (3.83.8) 30.9% (30.031.9)
Females onlya1,031,987 0.6% (0.60.6) 8.0% (7.78.3) 2.7% (2.72.8) 29.6% (28.630.5)
Males onlya1,081,915 0.1% (0.10.1) 1.0% (0.91.0) 4.8% (4.74.8) 40.1% (37.442.8)
Full siblings No. of pairsb
Both sexes 2,211,396 0.4% (0.40.4) 0.9% (0.91.0) 3.4% (3.43.4) 7.8% (7.28.4)
Female outcome female exposure 523,464 0.7% (0.70.7) 1.9% (1.62.1) 2.6% (2.52.6) 6.6% (5.87.4)
Female outcome male exposure 552,516 0.7% (0.70.8) 1.5% (1.31.7) 2.6% (2.62.7) 8.6% (6.211.0)
Male outcome female exposure 552,516 0.1% (0.10.1) 0.3% (0.20.4) 4.2% (4.24.3) 8.4% (7.69.3)
Male outcome male exposure 582,900 0.1% (0.10.1) 0.2% (0.20.3) 4.1% (4.04.2) 10.6% (7.913.3)
Half-siblings Pairsb
Both maternal and paternal 663,566 0.9% (0.80.9) 1.3% (1.21.3) 7.7% (7.67.8) 10.6% (9.911.4)
Notes: 95% CI 95% condence 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, rst 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 (10.911.9) 19.4 (18.620.4)
Relatives No. of pairsc
Monozygotic twins 9130 5.0 (1.516.9) 11.2 (3.042.2)
Dizygotic twins 17,350 0.6 (0.14.7) 1.0 (0.17.3)
Full siblings 2,211,396 2.4 (2.22.6) 2.8 (2.63.1)
Maternal half-siblings 332,486 1.4 (1.21.6) 1.4 (1.21.7)
Paternal half-siblings 331,080 1.5 (1.31.6) 1.5 (1.31.7)
Cousins parents full siblings 6,456,848 1.4 (1.31.5) 1.5 (1.41.6)
Cousins parents maternal half-siblings 472,212 1.2 (1.01.4) 1.3 (1.11.5)
Cousins parents paternal half-siblings 466,836 1.2 (1.01.4) 1.2 (1.01.4)
Notes: 95% CI 95% condence 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, rst with A as outcome
person and B as exposure person, then with B as outcome person and A as exposure person
Do borderline personality disorder and attention-decit/hyperactivity disorder co-aggregate in. . . 345
Content courtesy of Springer Nature, terms of use apply. Rights reserved
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
femalesADHD 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 signicant (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 denitions
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 denitions (Supplemental
Table 1b and d).
Test of familial factors
Analyses of full siblings with additional adjustment of
ADHD in the outcome person found OR signicantly
higher than 1 (aOR =1.4, 95% CI =1.21.5). Altogether,
ndings 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.
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 [4345]. This is in line with our results indicating
that the shared genetic origin of ADHD and BPD may reect
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-specic analyses
No. of individuals Crude odds ratio
(95% CI)
Adjusted odds ratioa
(95% CI)
Within femalesc1,031,987 14.9 (14.215.6) 19.1 (18.220.1) 0.047
Within malesc1,081,915 13.4 (11.915.0) 21.8 (19.324.5)
Full siblings No. of pairsd
Female outcome female exposure 523,464 2.7 (2.33.1) 2.9 (2.63.4) 0.087
Female outcome male exposure 552,516 2.1 (1.92.3) 2.5 (2.32.8)
Male outcome female exposure 552,516 3.5 (2.64.7) 3.9 (2.95.4) 0.683
Male outcome male exposure 582,900 2.8 (2.13.7) 3.6 (2.74.8)
Notes: 95% CI 95% condence 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, rst 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 traditionssupportedbylackevidenceofsex
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 registrieswe 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 proles sharing the same diag-
nosis and are likely to result in less specicity of diagnoses.
However, it also represents a more naturalistic result of the
relation between diagnoses given in the clinical environ-
ment. For our ADHD-denition we did not include ICD-10
diagnosis F98.8—“Other specied behavioral and emo-
tional disorders with onset usually occurring in childhood
and adolescence”—which include Attention-decit 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 denition, 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
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 accuratelythe 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 relativesreecting 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.
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
Conict 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 conict of interest.
Do borderline personality disorder and attention-decit/hyperactivity disorder co-aggregate in. . . 347
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... 9,12 There are also indications in the literature of ADHD and BPD sharing origin in terms of genetic and environmental factors. 13,14 It has been suggested that ADHD could be an early stage of BPD 15 and that the two conditions constitute different manifestations of a common underlying mechanism. 16 This is supported by findings of children diagnosed with ADHD being at increased risk of developing BPD 17,18 and of ADHDsymptom severity in childhood being positively associated with BPD-symptom severity in adulthood. ...
... 35 Two medical chart validation studies have been performed regarding BPD diagnosis in the NPR; a study by Kuoppis et al. found a positive predictive value of 100% using ICD-criteria, 36 another study by Kuja-Halkola et al. reported a positive predictive value of 81%. 14 We created a binary self-harm variable defined as having or not having self-harmed up to the age of 18 based on the combination of self-ratings in the Life History of Aggression questionnaire (LHA), and the Brief Obsessive Compulsive Scale (BOCS), and parental ratings in the Adult Behavior Check List (ABCL). See Table S2 for questionnaire details and Table S3 for distribution of responses. ...
Full-text available
Objective: Childhood Attention-Deficit /Hyperactivity Disorder (ADHD) is known to be associated with adult Borderline Personality Disorder (BPD). We investigated if any of the subdimensions of childhood ADHD, i.e., impulsivity, inattention, or hyperactivity was more prominent in this association. Methods: In a nation-wide cohort (N=13 330) we utilized parent reported symptoms of childhood ADHD and clinically ascertained adult BPD diagnoses. The summed total scores of ADHD symptoms and its three subdimensions were used and standardized for effect size comparison. Associations were analyzed using Cox regression with sex and birth-year adjustments. Secondary outcomes were BPD-associated traits (i.e., self-harm and substance use) analyzed using logistic- and linear regression respectively. Results: ADHD symptom severity was positively associated with BPD with a hazard ratio (HR) of 1.47 (95% confidence interval [CI]: 1.22-1.79) per standard deviation increase in total ADHD symptoms. Impulsivity was the most prominent subdimension with the only statistically significant association when analyzed in a model mutually adjusted for all ADHD subdimensions - HR for inattention: 1.15 (95% CI: 0.85-1.55), hyperactivity: 0.94 (95% CI: 0.69-1.26), impulsivity: 1.46 (95% CI: 1.12-1.91). In secondary analyses, weak positive associations were seen between total ADHD symptom score and self-harm and substance use. In analyses by subdimensions of ADHD, associations were weak and most prominent for inattention in the model with self-harm. Conclusion: Childhood ADHD symptoms were associated with subsequent development of BPD diagnosis and appeared to be driven primarily by impulsivity. Our findings are important for understanding the association between childhood symptoms of ADHD and subsequent BPD.
... However, the positive predictive value, i.e., proportion of diagnoses validated upon review, for the 26 BPD-diagnoses investigated was high regardless if structured interviews had been used or not, between 77% (based on DSM-criteria) and 100% (based on ICD-criteria); inter-rater agreement was between 85% (ICD-criteria) and 100% (DSMcriteria) [32]. Another validation study based on 70 medical charts with a BPD-diagnosis, and reported a positive predictive value of 81%, with an inter-rater agreement of 93% [33]. ...
... However, this study comes with caveats. First, although the NPR and BPD diagnostic codes are well-validated, the extent to which these comorbidities may be misdiagnosed is unclear [29,32,33]. However, one may argue that diagnoses, if not correctly diagnosed, may reflect levels of symptom presentation even if the full criteria of diagnosis is not met. ...
Full-text available
In one of the largest, most comprehensive studies on borderline personality disorder (BPD) to date, this article places into context associations between this diagnosis and (1) 16 different psychiatric disorders, (2) eight somatic illnesses, and (3) six trauma and adverse behaviors, e.g., violent crime victimization and self-harm. Second, it examines the sex differences in individuals with BPD and their siblings. A total of 1,969,839 Swedish individuals were identified from national registers. Cumulative incidence with 95% confidence intervals (CI) was evaluated after 5 years of follow-up from BPD diagnosis and compared with a matched cohort. Associations were estimated as hazard ratios (HR) with 95% CIs from Cox regression. 12,175 individuals were diagnosed with BPD (85.3% female). Individuals diagnosed with BPD had higher cumulative incidences and HRs for nearly all analyzed indicators, especially psychiatric disorders. Anxiety disorders were most common (cumulative incidence 95% CI 33.13% [31.48–34.73]). Other notable findings from Cox regressions include psychotic disorders (HR 95% CI 24.48 [23.14–25.90]), epilepsy (3.38 [3.08–3.70]), violent crime victimization (7.65 [7.25–8.06]), and self-harm (17.72 [17.27–18.19]). HRs in males and females with BPD had overlapping CIs for nearly all indicators. This indicates that a BPD diagnosis is a marker of vulnerability for negative events and poor physical and mental health similarly for both males and females. Having a sibling with BPD was associated with an increased risk for psychiatric disorders, trauma, and adverse behaviors but not somatic disorders. Clinical implications include the need for increased support for patients with BPD navigating the health care system.
... Kuja-Halkola et al. [38] investigated the co-occurrence and familial co-aggregation between clinically diagnosed ADHD and BPD in over two millions individuals born in Sweden between 1979 and 2001. The authors estimated the within-individual association between ADHD and BPD and the familial occurrence of ADHD and/or BPD in twins, siblings, half siblings and cousins, using an adjusted odds ratio (aOR). ...
... In other words, BPD and ADHD are both polygenic disorders with overlap of around 60% of the genetic variants involved [16,56]. The large population analysis from Kuja-Halkola et al. [38] confirms the high co-occurrence of ADHD and BPD on a population level with a 19.4 fold increased risk to suffer from BPD when having a diagnosis of ADHD. And it confirms that ADHD and BPD co-aggregate in relatives, confirming the probable genetic basis of this co-occurrence. ...
Full-text available
Background Overlap in symptom domains particularly in the field of impulsivity and emotional dysregulation in attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) have stimulated further research activities since our last review from 2014. Main body Disentangling features of impulsivity in ADHD and BPD revealed that impulsivity is a feature of both disorders with patients suffering from both ADHD and BPD having highest impulsivity ratings. BPD individuals have more problems using context cues for inhibiting responses and their impulsivity is stress-dependent, whereas ADHD patients have more motor impulsivity and therefore difficulties interrupting ongoing responses. For emotion regulation difficulties the ranking order ranges from ADHD to BPD to the comorbid condition, again with the patients suffering from both, ADHD and BPD, having the most pronounced emotion regulation problems. Environmental influences namely adverse childhood events were shown to be linked to both ADHD and BPD. Traumatic experiences seem independently linked to impulsivity features. Thus, some authors point to the risk of misdiagnosis during childhood and the necessity to screen for traumatic experiences in both patient groups. Genetic research confirmed genetic overlap of BPD with bipolar disorder (BD) and schizophrenic disorders, as well as genetic overlap of BD and ADHD. A population-based study confirmed the high co-occurrence and familial co-aggregation of ADHD and BPD. Interesting questions in the field of gene-environment-interactions are currently dealt with by genetic and epigenetic research. Few studies have investigated treatment strategies for the comorbid condition, though the issue is highly important for the management of patients suffering from both disorders and presenting with the highest symptom scores. Conclusion Research on the different impulsivity features might point to a necessity of disorder-specific treatment strategies in the field of impulse control. Future research is needed to base treatment decisions for the comorbid condition on an evidence basis.
... Furthermore, a number of papers have suggested that there is a link between childhood ADHD symptoms and borderline PD in adulthood (Miller et al., 2008;Smith & Samuel, 2017;Tiger et al., 2022). Shared genetic factors have been posited to explain this association (Kuja-Halkola et al., 2021). However, despite some common symptoms, such as impulsivity, and emotional dysregulation, attentional problems are more evident in those with ADHD compared to those with borderline PD (Koerting et al., 2016;O'Malley et al., 2016). ...
Full-text available
Objective: To estimate the prevalence of PDs according to Millon's evolution-based model among adult ADHD outpatients. Method: Cross-sectional study of consecutive patients referred to an adult ADHD clinic. PDs were evaluated with Millon Clinical Multiaxial Inventory-III (MCMI-III). Results: One-hundred-eighty-one participants had valid MCMI-III, of whom147 were diagnosed with ADHD. Mean age: 32.97, SD:11.56, females: 74 (50.3%). Among the 147 participants with ADHD, 29 (19.7%) did not meet criteria for any PD, 43 (29.3%) met the criteria for one PD, 34 (23.1%) for two PDs and the rest three or more. Most common PD was Dependent (n = 58) followed by Depressive (n = 45). Inattentive sub-type was associated with dependent PD, while combined type with antisocial, negativistic (passive/aggressive) and sadistic PD. Conclusion: Particular personality profiles were more common with different ADHD subtypes. Given the developmental origins of PD, further research may help identify possible links with childhood difficulties.
... ADHD was the only clinical diagnosis associated with PDs in univariate analysis. This result is in keeping with the results in a 2 million population-based study that concluded that ADHD increased the risk of BPD around 20 times, while the association was stronger with women [32]. In multivariate analysis, we found that ADHD lost significance, while CD showed a possible increase in the probability of PDs. ...
Full-text available
Self-harm (non-suicidal self-injury (NSSI) and suicidal behavior (SB)) is frequent display during adolescence. Patients with personality disorders (PDs) frequently self-harm. However, few studies have focused on the role of PDs in self-harming adolescents. In this study, we collected 79 adolescents hospitalized due to self-harm (88.6% female; 78.5% Caucasian) and divided them into two groups, with or without a diagnosis of PD. The socio-demographic and psychological-clinical data were collected through a structured interview by clinicians. Univariate, subgroup, and multiple logistic regression analyses were performed. Univariate analysis showed that adolescents with a PD and self-harm had (1) an older age at hospitalization (p < 0.01); (2) experienced physical and sexual abuse (p = 0.05, and p < 0.01, respectively); (3) ADHD (p = 0.05); (4) a greater number of SA (p < 0.01); and (5) probability of being a major NSSI patient (>20 lifetime NSSI episodes) (p < 0.01). After multivariate stratified analysis, the results indicated that an older age, and particularly major NSSI status were predictors of PD diagnosis. Early identification and a better understanding of the characteristics of adolescent PDs can assist clinicians in intervening earlier and developing more rational treatment strategies to reduce the long-term effects of PDs.
... This disease will not only affect an individual's learning function, but also bring emotional problems and daily life problems (Reimherr et al., 2020), such as marriage (Anastopoulos et al., 2009), and friendship (Pringsheim et al., 2015). At present, the prevalence of ADHD in children has exceeded 5% (Kuja-Halkola et al., 2021). At the same time, many children's academic performance is affected by the emergence of this disease (Matthys et al., 1999). ...
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Background With the popularity of computers, the internet, and the global spread of COVID-19, more and more attention deficit hyperactivity disorder (ADHD) patients need timely interventions through the internet. At present, there are many online intervention schemes may help these patients. It is necessary to integrate data to analyze their effectiveness.Objectives Our purpose is to integrate the ADHD online interventions trials, study its treatment effect and analyze its feasibility, and provide reference information for doctors in other institutions to formulate better treatment plans.Methods We searched PubMed, EMBASE and Cochrane libraries. We didn't limit the start date and end date of search results. Our last search was on December 1, 2021. The keyword is ADHD online therapy. We used the Cochrane bias risk tool to assess the quality of included studies, used the standardized mean difference (SMD) as an effect scale indicator to measure data. Random effects model, subgroup analysis were used to analyze the data.ResultsSix randomized controlled trials (RCTs) were identified, including 261 patients with ADHD. These studies showed that online interventions was more effective than waiting list in improving attention deficit and social function of adults and children with ADHD. The attention deficit scores of subjects were calculated in six studies. The sample size of the test group was 123, the sample size of the control group was 133, and the combined SMD was −0.73 (95% confidence interval: −1.01, −0.44). The social function scores of subjects were calculated in six studies. The sample size of the experimental group was 123 and the control group was 133. The combined SMD was −0.59 (95% confidence interval: −0.85, −0.33).Conclusions The results show that online interventions of ADHD may be an effective intervention. In the future, we need more online intervention researches to improve the symptoms of different patients, especially for some patients who have difficulties in accepting face-to-face treatment.
Background A joint, hierarchical structure of psychopathology and personality has been reported in adults but should also be investigated at earlier ages, as psychopathology often develops before adulthood. Here, we investigate the joint factor structure of psychopathology and personality in eight-year-old children, estimate factor heritability and explore external validity through associations with established developmental risk factors. Methods Phenotypic and biometric exploratory factor analyses with bifactor rotation on genetically informative data from the Norwegian Mother, Father, and Child Cohort (MoBa) study. The analytic sub-sample comprised 10 739 children (49% girls). Mothers reported their children's symptoms of depression (Short Moods and Feelings Questionnaire), anxiety (Screen for Anxiety Related Disorders), attention-deficit/hyperactivity disorder inattention and hyperactivity, oppositional-defiant disorder, conduct disorder (Parent/Teacher Rating Scale for Disruptive Behavior Disorders), and Big Five personality (short Hierarchical Personality Inventory for Children). Developmental risk factors (early gestational age and being small for gestational age) were collected from the Medical Birth Registry. Results Goodness-of-fit indices favored a p factor model with three residual latent factors interpreted as negative affectivity, positive affectivity, and antagonism, whereas psychometric indices favored a one-factor model. ADE solutions fitted best, and regression analyses indicated a negative association between gestational age and the p factor, for both the one- and four-factor solutions. Conclusion Correlations between normative and pathological traits in middle childhood mostly reflect one heritable and psychometrically interpretable p factor, although optimal fit to data required less interpretable residual latent factors. The association between the p factor and low gestational age warrants further study of early developmental mechanisms.
Objective This pre-registered systematic review synthesised and evaluated the existing literature on self-reported mental health and wellbeing of siblings of individuals with neurodevelopmental conditions (NDCs). Methods From 2437 identified studies published 2000–2022, 81 studies were included: 14 population- or cohort-based, 39 quantitative, 7 mixed method, and 21 qualitative outcome studies. Results Seven sibling mental health (any psychiatric disorder, anxiety, depression, bipolar disorder, schizophrenia, internalising and externalising difficulties) and five wellbeing indicators were identified (quality of life, emotional adjustment, social wellbeing, somatic/physical wellbeing, and resilience/growth). Overall, siblings had increased risk of any psychiatric disorder, but they also reported experiences of growth and resilience, primarily in qualitative studies. 41 risk factors and 24 resilience factors associated with these outcomes were identified; the most frequently cited risk factor was symptom severity of the NDC sibling, while the most common resilience factor was adaptive/active coping at the individual sibling level. Studies showed high methodological heterogeneity and 90 different self-report measures were used. Conclusions Sibling mental health indictors are heterogeneous and cumulative risk factors may result in poorer wellbeing. There is a need for consistent reporting of family and sibling characteristics, a strengths-based approach to assessment, and identification of protective and resilience-promoting factors.
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Background: Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) have partially overlapping symptom profiles and are highly comorbid in adults. However, whether the behavioral similarities correspond to shared neurobiological substrates is not known. Methods: An overlapping meta-analysis of 58 ADHD and 66 BPD whole-brain articles incorporating observations from 3401 adult patients and 3238 healthy participants was performed by Seed-based d Mapping. Brain maps were subjected to meta-analytic connectivity modeling and data-driven functional decoding analyses to identify associated neural circuit alterations and relations to behavioral dimensions. Results: Both groups exhibited hypo-activated abnormalities in the left inferior parietal lobule, and altered clusters of the bilateral superior temporal gyrus were disjunctive in ADHD and BPD. No overlapping structural abnormalities were found. Multimodal alterations of ADHD were located in the right putamen and of BPD in the left orbitofrontal cortex. Conclusions: The transdiagnostic neural bases of ADHD and BPD in temporo-parietal circuitry may underlie overlapping problems of behavioral control, while disorder-specific substrates in fronto-striatal circuitry may account for their distinguishing features in motor and emotion domains respectively.
This review aims to establish the cognitive processing of patients with attention-deficit hyperactive disorder (ADHD) across age. Functional magnetic resonance imaging (fMRI) studies on children and adult populations were conducted, thus delineating deficits that could have been maintained and ameliorated across age. This allowed for the examination of the correlation between patterns of brain activation and the corresponding development of functional heterogeneity in ADHD. A systematic literature search of fMRI studies on ADHD was conducted using the PubMed and Scopus electronic databases based on PRISMA guidelines. References and citations were verified in Scopus database. The present study has identified 14 studies on children, 16 studies on adults, and one study on both populations of ADHD consisting of 1,371 participants. Functional heterogeneity is present in ADHD across age, which can manifest either as different brain activation patterns, intra-subject variability, or both. This is shown in the increased role of the frontal regions and the specialized network in adults with ADHD from inefficient non-specific activation in childhood. Functional heterogeneity may manifest when delayed maturation is insufficient to normalize frontal lobe functions.
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Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77–22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80–32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21–5.85) and full siblings (OR=4.59, 95% CI: 4.39–4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.
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Deficient cognitive top-down executive control has long been hypothesized to underlie inattention and impulsivity in attention-deficit/hyperactivity disorder (ADHD). However, top-down cognitive dysfunction explains a modest proportion of the ADHD phenotype whereas the salience of emotional dysregulation is being noted increasingly. Together, these two types of dysfunction have the potential to account for more of the phenotypic variance in patients diagnosed with ADHD. We develop this idea and suggest that top-down dysregulation constitutes a gradient extending from mostly non-emotional top-down control processes (i.e., “cool” executive functions) to mainly emotional regulatory processes (including “hot” executive functions). While ADHD has been classically linked primarily to the former, conditions involving emotional instability such as borderline and antisocial personality disorder are closer to the other extreme. In this model, emotional subtypes of ADHD are located at intermediate levels of this gradient. Neuroanatomically, gradations in “cool” processing appear to be related to prefrontal dysfunction involving dorsolateral prefrontal cortex and caudal anterior cingulate cortex, while “hot” processing entails orbitofrontal cortex and rostral anterior cingulate cortex. A similar distinction between systems related to non-emotional and emotional processing appears to hold for the basal ganglia and the neuromodulatory effects of the dopamine system. Overall we suggest that these two systems could be divided according to whether they process non-emotional information related to the exteroceptive environment (associated with “cool” regulatory circuits) or emotional information related to the interoceptive environment (associated with “hot” regulatory circuits). We propose that this framework can integrate ADHD, emotional traits in ADHD, borderline and antisocial personality disorders into a related cluster of mental conditions.
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When studying the association between an exposure and an outcome, it is common to use regression models to adjust for measured confounders. The most common models in epidemiologic research are logistic regression and Cox regression, which estimate conditional (on the confounders) odds ratios and hazard ratios. When the model has been fitted, one can use regression standardization to estimate marginal measures of association. If the measured confounders are sufficient for confounding control, then the marginal association measures can be interpreted as poulation causal effects. In this paper we describe a new R package, stdReg, that carries out regression standardization with generalized linear models (e.g. logistic regression) and Cox regression models. We illustrate the package with several examples, using real data that are publicly available.
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Objective Attention-deficit/hyperactivity disorder (ADHD) is more frequent in males than in females. The “female protective effect” posits that females undergo greater exposure to etiological factors than males in order to develop ADHD, leading to the prediction that relatives of females with ADHD will display more ADHD behaviors. We thus tested whether cotwins of females displaying extreme ADHD traits would display more ADHD traits than cotwins of males displaying extreme ADHD traits. Method Parents of approximately 7,000 pairs of nonidentical twins in Sweden, and approximately 4,000 pairs of twins in England and Wales, completed dimensional assessments of ADHD traits. Probands were selected on the basis of scoring within the highest 10% of the distribution in each sample. Dimensional scores of cotwins of probands, as well as the categorical recurrence rate, were investigated by proband sex. Results Cotwins of female probands displayed higher mean ADHD trait scores (mean = 0.62−0.79) than cotwins of male probands (mean = 0.38−0.55) in both samples. This trend was significant in the Swedish sample (p < .01) and when the 2 samples were merged into a single, larger sample (p < .001). When the samples were merged, there was also a significant association between proband sex and cotwin’s categorical status, with more cotwins of female probands also being probands than cotwins of male probands. Conclusion These findings support a female protective effect against ADHD behaviors, suggesting that females require greater exposure to genetic and environmental factors associated with ADHD in order to develop the condition.
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The primary aim of the Swedish national population registration system is to obtain data that (1) reflect the composition, relationship and identities of the Swedish population and (2) can be used as the basis for correct decisions and measures by government and other regulatory authorities. For this purpose, Sweden has established two population registers: (1) The Population Register, maintained by the Swedish National Tax Agency (“Folkbokföringsregistret”); and (2) The Total Population Register (TPR) maintained by the government agency Statistics Sweden (“Registret över totalbefolkningen”). The registers contain data on life events including birth, death, name change, marital status, family relationships and migration within Sweden as well as to and from other countries. Updates are transmitted daily from the Tax Agency to the TPR. In this paper we describe the two population registers and analyse their strengths and weaknesses. Virtually 100 % of births and deaths, 95 % of immigrations and 91 % of emigrations are reported to the Population Registers within 30 days and with a higher proportion over time. The over-coverage of the TPR, which is primarily due to underreported emigration data, has been estimated at up to 0.5 % of the Swedish population. Through the personal identity number, assigned to all residents staying at least 1 year in Sweden, data from the TPR can be used for medical research purposes, including family design studies since each individual can be linked to his or her parents, siblings and offspring. The TPR also allows for identification of general population controls, participants in cohort studies, as well as calculation of follow-up time.
Objective: The authors describe personality development and disorders in relation to symptoms of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders. Method: Consecutive adults referred for neuropsychiatric investigation (N=240) were assessed for current and lifetime ADHD and autism spectrum disorders and completed the Temperament and Character Inventory. In a subgroup of subjects (N=174), presence of axis II personality disorders was also assessed with the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II). Results: Patients with ADHD reported high novelty seeking and high harm avoidance. Patients with autism spectrum disorders reported low novelty seeking, low reward dependence, and high harm avoidance. Character scores (self-directedness and cooperativeness) were extremely low among subjects with neuropsychiatric disorders, indicating a high overall prevalence of personality disorders, which was confirmed with the SCID-II. Cluster B personality disorders were more common in subjects with ADHD, while cluster A and C disorders were more common in those with autism spectrum disorders. The overlap between DSM-IV personality disorder categories was high, and they seem less clinically useful in this context. Conclusions: ADHD and autism spectrum disorders are associated with specific temperament configurations and an increased risk of personality disorders and deficits in character maturation.
Objective Although many studies document an association between attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID), little is known about the etiology of this comorbidity and how it should be addressed in clinical settings. We sought to clarify this issue. Method All individuals born in Sweden between 1987 and 2006 (n = 2,049,587) were identified using the Medical Birth Register (MBR). From this we selected 7 cohorts of relatives: 1,899,654 parent–offspring pairs, 4,180 monozygotic twin pairs, 12,655 dizygotic twin pairs, 914,848 full sibling pairs, 136,962 maternal half-sibling pairs, 134,502 paternal half-sibling pairs, and 2,790,164 full cousin pairs. We used within-individual and within-family analyses to assess the association between ADHD and ID. Results Individuals with ID were at increased risk for ADHD compared to those without ID, and relatives of participants with ID were at increased risk of ADHD compared with relatives of those without ID. The magnitude of this association was positively associated with the fraction of the genome shared by the relative pair and was lower for severe compared with mild and moderate ID. Model-fitting analyses demonstrated that 91% of the correlation between the liabilities of ADHD and ID was attributable to genetic factors. Conclusion These data provide evidence that nearly all of the comorbidity between ADHD and ID can be attributed to genetic factors, which has implications for diagnostic practice.
Objective. Children with attention-deficit/hyperactivity disorder (ADHD) display alterations in both emotion reactivity and regulation. One mechanism underlying such alternations may be reduced coherence among emotion systems (i.e., autonomic, facial affect). The present study sought to examine this. Method. 100 children (50 with ADHD combined presentation), aged 7 to 11 years (62% male, 78% White), completed an emotion induction and suppression task. This task was coded for facial affect behavior across both negative and positive emotion eliciting task conditions. Electrocardiogram and impedance cardiography data were acquired throughout the task. Time-linked coherence of facial affect behavior and autonomic reactivity and regulation were examined during the induction conditions using Hierarchical Linear Modeling. Results. While ADHD and typically developing children did not differ with respect to rates of facial affect behavior displayed (all F<2.09, p> .29), the ADHD group exhibited reduced coherence between facial affect behavior and an index of parasympathetic functioning (i.e., respiratory sinus arrhythmia [RSA]; γ10=-0.03, SE=0.02, t(138)=-1.96, p=0.05). In contrast, children in the control group displayed a significant, positive (γ10=0.06, SE=0.01, t(138)=4.07, p< .001) association between facial affect behavior and RSA. Conclusions. Children with ADHD may receive conflicting emotional signals at the levels of facial affective behavior and parasympathetic functioning when compared to typically developing youth. Weakened coherence among these emotion systems may be an underlying mechanism of emotion dysregulation in ADHD. Implications for etiology and treatment are discussed. KEY WORDS: ADHD, autonomic reactivity, emotion regulation, facial affect
Importance Suicide attempts are common in individuals with eating disorders. More precise understanding of the mechanisms underlying their concomitant occurrence is needed.Objective To examine the association between eating disorders and suicide attempts and whether familial risk factors contribute to the association.Design, Setting, and Participants A Swedish birth cohort including individuals born in Sweden between January 1, 1979, and December 31, 2001, was followed up from age 6 years to December 31, 2009 (N = 2 268 786). Information was acquired from Swedish national registers. All individuals were linked to their biological full siblings, maternal half siblings, paternal half siblings, full cousins, and half cousins. Data analysis was conducted from October 5, 2014, to April 28, 2015.Main Outcomes and Measures Eating disorders were captured by 3 variables (any eating disorder, anorexia nervosa, and bulimia nervosa) identified by any lifetime diagnoses recorded in the registers. Suicide attempts were defined as any suicide attempts, including death by suicide, recorded in the registers. We examined the association between eating disorders and death by suicide separately, but the study was underpowered to explore familial liability for this association.Results Of 2 268 786 individuals, 15 457 females (1.40% of all females) and 991 males (0.09% of all males) had any eating disorder, 7680 females (0.70%) and 453 males (0.04%) had anorexia nervosa, and 3349 females (0.30%), and 61 males (0.01%) had bulimia nervosa. Individuals with any eating disorder had an increased risk (reported as odds ratio [95% CI]) of suicide attempts (5.28 [5.04-5.54]) and death by suicide (5.39 [4.00-7.25]). The risks were attenuated but remained significant after adjusting for comorbid major depressive disorder, anxiety disorder, and substance use disorder (suicide attempts: 1.82 [1.72-1.93]; death by suicide: 2.04 [1.49-2.80]). Similar results were found for anorexia nervosa (suicide attempts: crude, 4.42 [4.12-4.74] vs adjusted, 1.70 [1.56-1.85]; death by suicide: crude, 6.46 [4.38-9.54] vs adjusted, 2.67 [1.78-4.01]) and bulimia nervosa (suicide attempts: crude, 6.26 [5.73-6.85] vs adjusted, 1.88 [1.68-2.10]; death by suicide: crude, 4.45 [2.44-8.11] vs adjusted, 1.48 [0.81-2.72]). Individuals (index) who had a full sibling with any eating disorder had an increased risk of suicide attempts (1.41 [1.29-1.53]). The risk was attenuated for any eating disorder in more-distant relatives (maternal half siblings, 1.10 [0.90-1.34]; paternal half siblings, 1.21 [0.98-1.49]; full cousins, 1.11 [1.06-1.18]; half cousins, 0.90 [0.78-1.03]). This familial pattern remained stable after adjusting for the index individuals’ eating disorders. Similar patterns were found for anorexia nervosa and bulimia nervosa.Conclusions and Relevance These results suggest an increased risk of suicide attempts in individuals with lifetime eating disorders and their relatives. The pattern of familial coaggregation suggests familial liability for the association between eating disorders and suicide. Psychiatric comorbidities partially explain this association, suggesting particularly high-risk presentations.