Serum Calcium, 25-Hydroxyvitamin D, and Parathyroid Hormone Levels in Relation to Aneurysmal Subarachnoid Hemorrhage

Elevated serum calcium (S-Ca), 25-hydroxyvitamin D (S-25OHD), and parathyroid hormone (S-PTH) levels have been associated with risk of aneurysmal subarachnoid hemorrhage (SAH) in observational studies. However, whether these associations are causal is unclear. The objective of the present study was to determine whether genetically predicted S-Ca, S-25OHD, and S-PTH levels are causally associated with aneurysmal SAH using a Mendelian randomization design. Analyses were performed using summary-level data for genetic variants associated with S-Ca, S-25OHD, and S-PTH concentrations. Summary data for aneurysmal SAH were adopted from a genome-wide association study (GWAS) on intracranial aneurysm (n = 79,429 individuals, 69% of the cases had aneurysmal SAH). The inverse variance-weighted approach was adopted as the primary analyses. For sensitivity analyses, the weighted median and MR-Egger approaches were adopted. Genetically predicted S-Ca and S-PTH levels were associated with aneurysmal SAH in the primary analyses. The odds ratios (ORs) of aneurysmal SAH were 1.96 (95% CI: 1.003–3.812; P = 0.049) and 1.495 (95% CI: 1.058–2.114; P = 0.023) for one SD increase of genetically predicted S-Ca and S-PTH levels, respectively. Genetically predicted S-25OHD concentration was not associated with aneurysmal SAH (per 1 SD increase in S-25OHD: OR = 0.92; 95% CI, 0.78–1.09; P = 0.332). Sensitivity analysis yielded similar results, and no evidence of pleiotropy was observed. Our results indicated that higher genetically predicted S-Ca and S-PTH levels may increase the risk of aneurysmal SAH.