Genetically Determined Smoking Behavior and Risk of Nontraumatic Subarachnoid Hemorrhage

Abstract

Background and Purpose: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH. Methods: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate ( P <5 ×10 − 8 ) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods. Results: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20–1.21]; P <0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03–1.17]; P =0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15–2.31]; P =0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13–2.17]; P =0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06–2.86]; P =0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P =0.39; MR Pleiotropy Residual Sum and Outlier global test P =0.69). Conclusions: These findings provide evidence for a causal link between smoking and the risk of SAH.

A two-sample Mendelian randomization analysis of modifiable risk factors and intracranial aneurysms

“…In a case–control study including 4701 patients with 6411 IAs, the authors found that current cigarette smoking, smoking intensity, and smoking duration were significantly associated with ruptured IAs at presentation 4 . A recently published MR study using data from the UK Biobank also showed a causal relationship between smoking and SAH 12 . This MR study provided genetic evidence for the causal relationship between smoking and IA.…”

“…Above-mentioned confounding and reverse causation are avoided in MR studies since genetic alleles are randomly assorted during conception 10 . Limited evidence from MR for ICAs has been reported 11 , 12 . A MR study using the data from UK-Biobank showed a causal link between smoking and the risk of SAH 12 .…”

“…Limited evidence from MR for ICAs has been reported 11 , 12 . A MR study using the data from UK-Biobank showed a causal link between smoking and the risk of SAH 12 . While, another MR study found that diabetes mellitus and obesity were not causally associated with IAs 11 .…”

Mendelian Randomization in Stroke: A Powerful Approach to Causal Inference and Drug Target Validation

“…In other MR studies, Larsson et al (2019aLarsson et al ( , 2020c confirmed the association between smoking initiation and the risk of any ischemic stroke, LAS and SVS, but did not find an association with cardioembolic stroke (CES) or ICH. In a one-sample MR study using the UK Biobank, Acosta et al (2021) confirmed an association between genetic propensity to smoke and risk of nontraumatic subarachnoid hemorrhage.…”

Association of gut microbiome with risk of intracranial aneurysm: a mendelian randomization study

“…It has been realized by more and more neurosurgeons that environmental factors act a more significant role than inherited factors in the pathophysiology of IAs [ 15 , 16 ]. Pyysalo et al have reported the association of IAs with oral bacteria, suggesting a link between aneurysms and bacteria [ 17 ].…”