Abstract 66: Causal Associations Between Genetically-determined Smoking and Risk of Subarachnoid Hemorrhage

Abstract

Introduction: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and SAH has not been established. We leveraged the causal properties of mutation-disease associations to test the hypothesis that smoking is causally linked to SAH. Methods: We conducted a one-sample Mendelian Randomization (MR) study within the UK Biobank, a prospective, population-based observational study. We restricted the analysis to study participants with genetically-confirmed European ancestry. SAH cases were ascertained using previously validated codes. As the instrument, we built a polygenic risk score (PRS) using independent (R2<0.1) genetic variants known to be associated (p<5x10-8) with smoking. For the primary MR analysis, we implemented the ratio method using the estimates obtained from testing the PRS for association with risk of SAH and smoking. In secondary analyses, we implemented the inverse-variance weighted (IVW) and weighted median (WM) methods. Pleiotropy was assessed via the MR-Egger approach. Results: We included a total of 408,622 individuals in this study (mean age 57 [SD 8], female sex 220,944 [54%]). Of these, 132,568 (32%) ever smoked regularly and 904 (0.22%) had an SAH. Each additional standard deviation of the smoking PRS was associated with a 9% increased risk of SAH (OR 1.09, 95%CI 1.03-1.17; p=0.006) and 21% increased risk of smoking (OR 1.21, 95%CI 1.2-1.21; p=1x10-16). In the primary analysis, genetically-determined smoking was associated with a 63% increase in risk of SAH (OR 1.63, 95%CI 1.15-2.30; p=0.006). Secondary analyses using the IVW method (OR 1.57, 95%CI 1.13-2.17; p=0.007) and the WM method (OR 1.74, 95%CI 1.06-2.86; p=0.028) yielded comparable results. There was no significant pleiotropy (MR-Egger intercept p=0.38). Conclusion: Genetically-determined smoking is strongly associated with the risk of SAH. These findings provide evidence for a causal link between smoking and the occurrence of this often-debilitating condition. Interventions aimed at reducing smoking behavior could offer significant benefits, especially to those at high risk of SAH.