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Background Serum lipids are causally involved in the occurrence of atherosclerosis, but their roles in cerebral small vessel disease remain unclear. This study aimed to investigate the causal roles of lipid or apolipoprotein traits in cerebral small vessel disease and to determine the effects of lipid‐lowering interventions on this disease. Methods and Results Data on genetic instruments of lipids/apolipoproteins, as well as characteristic cerebral small vessel disease manifestations, including small vessel stroke (SVS) and white matter hyperintensity (WMH), were obtained from publicly genome‐wide association studies. Through 2‐sample Mendelian randomization analyses, it was found that decreased levels of high‐density lipoprotein cholesterol (odds ratio [OR], 0.85, P=0.007) and apolipoprotein A‐I (OR, 0.83, P=0.005), as well as increased level of triglycerides (OR, 1.16, P=0.025) were associated with a higher risk of SVS. A low level of high‐density lipoprotein cholesterol (OR, 0.93, P=0.032) was associated with larger WMH volume. Specifically, the genetically determined expressions of lipid fractions in various size‐defined lipoprotein particles were more closely related to the risk of SVS than WMH. Moreover, it was found that the hypertension trait ranked at the top in mediating the causal effect of hyperlipidemia on SVS and WMH by using Mendelian randomization‐based mediation analysis. For drug‐target Mendelian randomization, the low‐density lipoprotein cholesterol‐reducing genetic variation alleles at HMGCR and NL1CL1 genes and the high‐density lipoprotein cholesterol‐raising genetic variation alleles at the CETP gene were predicted to decrease the risk of SVS. Conclusions The present Mendelian randomization study indicates that genetically determined hyperlipidemia is closely associated with a higher risk of cerebral small vessel disease, especially SVS. Lipid‐lowering drugs could be potentially considered for the therapies and preventions of SVS rather than WMH.

Background Chitinase‐3 like protein 1 (CHI3L1, YKL‐40) was reported to be implicated in the development of ischemic stroke, but whether the association between them was causal remained unclear. We conducted a 2‐sample Mendelian randomization study to explore the associations of genetically determined plasma YKL‐40 with ischemic stroke and its subtypes (large artery stroke, small vessel stroke, and cardioembolic stroke). Methods and Results Based on genome‐wide association study data of 3394 European‐descent individuals, we selected 13 single‐nucleotide polymorphisms associated with plasma YKL‐40 as genetic instruments. Summary data about ischemic stroke and its subtypes were obtained from the Multiancestry Genome‐wide Association Study of Stroke Consortium, involving 34 217 ischemic stroke cases and 406 111 controls of European ancestry. We used the inverse‐variance weighted method followed by a series of sensitivity analyses to assess the causal associations of plasma YKL‐40 with ischemic stroke and its subtypes. The primary analysis showed that genetically determined high YKL‐40 levels were associated with increased risks of large artery stroke (odds ratio [OR], 1.08 [95% CI, 1.04–1.12]; P=1.73×10−4) and small vessel stroke (OR, 1.05 [95% CI, 1.01–1.09]; P=7.96×10−3) but not with ischemic stroke or cardioembolic stroke. Sensitivity analyses further confirmed these associations, and Mendelian randomization‐Egger indicated no evidence of genetic pleiotropy. In addition, supplementary analysis based on the summary data from the Olink proximity extension assay cardiovascular I (Olink CVD‐I) panel showed that high YKL‐40 levels were positively associated with the risks of large artery stroke (OR, 1.15 [95% CI, 1.08–1.22]; P=4.16×10−6) but not with small vessel stroke. Conclusions Genetically determined high plasma YKL‐40 levels were causal associated with increased risks of large artery stroke.

Background and Purpose: The causal effect of insulin resistance on small vessel stroke and Alzheimer's disease (AD) was controversial in previous studies. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect of insulin resistance on small vessel stroke and AD., Methods: We selected 12 single-nucleotide polymorphisms (SNPs) associated with fasting insulin levels and five SNPs associated with "gold standard" measures of insulin resistance as instrumental variables in MR analyses. Summary statistical data on SNP-small vessel stroke and on SNP-AD associations were derived from studies by the Multi-ancestry Genome-Wide Association Study of Stroke consortium (MEGASTROKE) and the Psychiatric Genomics Consortium-Alzheimer Disease Workgroup (PGC-ALZ) in individuals of European ancestry. Two-sample MR estimates were conducted with inverse-variance-weighted, robust inverse-variance-weighted, simple median, weighted median, weighted mode-based estimator, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods., Results: Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke (OR 1.23, 95% confidence interval [CI] 1.05-1.44, p = 0.01 using fasting insulin; OR 1.25, 95% CI 1.07-1.46, p = 0.006 using gold standard measures of insulin resistance) and AD (OR 1.13, 95% CI 1.04-1.23, p = 0.004 using fasting insulin; OR 1.02, 95% CI 1.00-1.03, p = 0.03 using gold standard measures of insulin resistance) using the inverse-variance-weighted method. No evidence of pleiotropy was found using MR-Egger regression., Conclusion: Our findings provide genetic support for a potential causal effect of insulin resistance on small vessel stroke and AD., (© 2021 European Academy of Neurology.)