WSO - March 2023 - 351

Du et al.
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Table 1. Univariable MR (IVW) for ADHD on CAD, CAD on LAS, CAD on CES, ADHD on age of smoking initiation, age of
smoking initiation on LAS, and age of smoking initiation on CES.
Exposure
ADHD
CAD
CAD
ADHD
Age of smoking initiation
Age of smoking initiation
Outcome
CAD
LAS
CES
Age of smoking initiation
LAS
CES
No. of SNPs
9
40
40
9
6
6
OR
1.11
1.43
1.13
0.94
0.29
1.79
95% CI
1.01, 1.22
1.17, 1.75
1.02, 1.24
0.90, 0.99
0.09, 0.91
0.68, 4.71
P-value
0.033
<0.001
0.016
0.013
0.034
0.239
IVW: inverse variance-weighted method; ADHD: attention-deficit/hyperactivity disorder; CAD: coronary artery disease; LAS: large-artery
atherosclerotic stroke; CES: cardioembolic stroke; SNP: single-nucleotide polymorphism; OR: odds ratio; 95% CI = 95% confidence interval.
Figure 4. Relationships among ADHD, LAS, and potential
mediators between them using multivariable Mendelian
randomization.
of ischemic stroke, especially LAS. MVMR results suggest
the mediating role of ADHD in the causal relationship
between age of smoking initiation and LAS; and CAD may
be a potential mediator of the association between ADHD
and ischemic stroke.
SNP: single-nucleotide polymorphism; ADHD: attention-deficit/
hyperactivity disorder; CAD: coronary artery disease; LAS: large-artery
atherosclerotic stroke.
Dashed lines represent indirect effects. (a) ADHD affects LAS through
its effect on CAD rather than through a direct effect on LAS. (b)
ADHD affects LAS directly, while age of smoking initiation affects LAS
through its effect on ADHD.
potentially affected LAS directly, while age of smoking
initiation affected LAS through its effect on ADHD.
Discussion
To our knowledge, the present study is the first to explore
causality and possible mediators between ADHD and
ischemic stroke. We used two-sample MR to detect the
effect of ADHD on ischemic stroke and its subtypes, providing
evidence that ADHD causes an increase in the risk
Some previous observational studies reported that
ADHD is associated with smoking and earlier initiation
age.30,36,37 Other studies have provided evidence for a
causal association between smoking and ischemic
stroke.31,32,38 Our results show that the effect of age of
smoking initiation on LAS was attenuated when simultaneously
assessing the effects of ADHD and age of smoking
initiation on LAS, indicating that ADHD may be a potential
mediator of the causal relationship between age of smoking
initiation and LAS. As nicotine can improve attention,
smoking may be a form of " self-medication " for ADHD
patients.39 However, there is growing evidence that smoking
may actually worsen mental health through neuroadaptations
arising from chronic smoking.40 Our findings
support the latter view, suggesting that early initiation of
smoking in ADHD patients is not only detrimental to physical
health, but may also be detrimental to mental health.
When we simultaneously assessed the effects of ADHD
and CAD on ischemic stroke subtypes (LAS and CES)
using MVMR, our results suggested a mediating role of
CAD in the causal relationship between ADHD and
ischemic stroke subtypes (LAS and CES). CAD begins
with injury to the inner layer of a coronary artery. Once the
inner wall of an artery is damaged, atherosclerosis occurs,
where plaques composed of cholesterol and other cellular
wastes accumulate. If the plaques break or rupture, platelets
will clump here, trying to repair the artery. This clump can
block the arteries and cause LAS or CES when flowing to
the brain. However, we emphasize that this exploration of
CAD as a possible mediator should be interpreted with caution
since we could not unravel the effects of ADHD and
CAD on LAS or CES. Further research is required to provide
more evidence.
International Journal of Stroke, 18(3)

WSO - March 2023

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