Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study

Abstract

Background: Previous observational studies reported that a lower serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with a higher burden of cerebral small vessel disease (cSVD). The causality of this association is uncertain, but it would be clinically important, given that 25(OH)D can be a target for intervention. We tried to examine the causal effect of 25(OH)D concentration on cSVD-related phenotypes using a Mendelian randomization approach.

Methods: Genetic instruments for each serum 25(OH)D concentration and cSVD-related phenotypes (lacunar stroke, white matter hyperintensity, cerebral microbleeds, and perivascular spaces) were derived from large-scale genome-wide association studies. We performed 2-sample Mendelian randomization analyses with multiple post hoc sensitivity analyses. A bidirectional Mendelian randomization approach was also used to explore the possibility of reverse causation.

Results: We failed to find any significant causal effect of 25(OH)D concentration on cSVD-related phenotypes (odds ratio [95% CI], 1.00 [0.87-1.16], 1.01 [0.96-1.07], 1.06 [0.85-1.33], 1.00 [0.97-1.03], 1.02 [0.99-1.04], 1.01 [0.99-1.04] for lacunar stroke, white matter hyperintensity, cerebral microbleeds, and white matter, basal ganglia, hippocampal perivascular spaces, respectively). These results were reproduced in the sensitivity analyses accounting for genetic pleiotropy. Conversely, when we examined the effects of cSVD phenotypes on 25(OH)D concentration, cerebral microbleeds were negatively associated with 25(OH)D concentration (0.94 [0.92-0.96]).

Conclusions: Given the adequate statistical power (>0.8) of the analyses, our findings suggest that the previously reported association between 25(OH)D concentration and cSVD phenotypes might not be causal and partly attributed to reverse causation.

Keywords: Mendelian randomization; brain; cerebral small vessel disease; polymorphism, single nucleotide; vitamin D deficiency.

Figure 1.

Results of the Mendelian randomization analysis for the effect of the 25(OH)D concentration on cerebral small vessel disease phenotypes. A, Lacunar stroke; (B) white matter hyperintensity volume; (C) cerebral microbleeds; (D) white matter perivascular spaces; (E) basal ganglia perivascular spaces; and (F) hippocampal perivascular spaces. 25(OH)D indicates 25-hydroxyvitamin D; IVW, inverse-variance weighted; and SNP, single-nucleotide polymorphism.

Figure 2.

Scatter plot of the Mendelian randomization analysis results for the effect of the 25(OH)D concentration on cerebral small vessel disease phenotypes. A, Lacunar stroke; (B) white matter hyperintensity volume; (C) cerebral microbleeds; (D) white matter perivascular spaces; (E) basal ganglia perivascular spaces; and (F) hippocampal perivascular spaces. 25(OH)D indicates 25-hydroxyvitamin D; IVW, inverse-variance weighted; and SNP, single-nucleotide polymorphism.

Figure 3.

Results of reverse Mendelian randomization analysis for the effect of cerebral small vessel disease phenotypes on the 25(OH)D concentration. A, Lacunar stroke; (B) white matter hyperintensity volume; (C) cerebral microbleeds; (D) white matter perivascular spaces; (E) basal ganglia perivascular spaces; and (F) hippocampal perivascular spaces. 25(OH)D indicates 25-hydroxyvitamin D; IVW, inverse-variance weighted; and SNP, single-nucleotide polymorphism.

Figure 4.

Scatter plot of the reverse Mendelian randomization analysis results for the effect of cerebral small vessel disease phenotypes on the 25(OH)D concentration. A, Lacunar stroke; (B) white matter hyperintensity volume; (C) white matter perivascular spaces; (D) basal ganglia perivascular spaces; and (E) hippocampal perivascular spaces. 25(OH)D indicates 25-hydroxyvitamin D; IVW, inverse-variance weighted; and SNP, single-nucleotide polymorphism.