Data from: Diabetes mellitus, glycemic traits, and cerebrovascular disease: A Mendelian randomization study

Objective: We employed Mendelian randomization (MR) to explore
the effects of genetic predisposition to type 2 diabetes (T2D),
hyperglycemia, insulin resistance, and β-cell dysfunction on risk
of stroke subtypes and related cerebrovascular phenotypes.
Methods: We selected instruments for genetic predisposition to
T2D (74,124 cases, 824,006 controls), HbA1c levels (n=421,923), fasting
glucose levels (n=133,010), insulin resistance (n=108,557),
and β-cell dysfunction (n=16,378) based on published genome-wide
association studies. Applying two-sample MR, we examined associations with
ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage
(1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery,
cardioembolic, small vessel stroke), as well as with related phenotypes
(carotid atherosclerosis, imaging markers of cerebral white matter
integrity, and brain atrophy).  Results: Genetic
predisposition to T2D and higher HbA1c levels were associated with higher
risk of any ischemic stroke, large artery stroke, and small vessel stroke.
Similar associations were also noted for carotid atherosclerotic plaque,
fractional anisotropy, a white matter disease marker, and markers of brain
atrophy. We further found associations of genetic predisposition to
insulin resistance with large artery and small vessel stroke, whereas
predisposition to β-cell dysfunction was associated with small
vessel stroke, intracerebral hemorrhage, lower grey matter volume, and
total brain volume. Conclusions: This study supports causal
effects of T2D and hyperglycemia on large artery and small vessel
stroke. We show associations of genetically predicted insulin
resistance and β-cell dysfunction with large artery and small
vessel stroke that might have implications for anti-diabetic treatments
targeting these mechanisms. Classification of Evidence: This
study provides Class II evidence that genetic predisposition to T2D and
higher HbA1c levels are associated with a higher risk of large artery and
small vessel ischemic stroke.