Drug classes affecting intracranial aneurysm risk: genetic correlation and Mendelian randomization

Abstract and key words Background There is no non-invasive treatment option to prevent aneurysmal subarachnoid hemorrhage (ASAH) caused by intracranial aneurysm (IA) rupture. We aimed to identify drug classes that may affect liability to IA using a genetic approach. Methods We obtained genome-wide association summary statistics for unruptured IA (N=2,140 cases), ASAH (N=5,140 cases), and the combined group (N=7,495 cases; N=71,934 controls in all groups), and drug usage from 23 drug classes (N up to 320,000) based on European-ancestry cohorts. We calculated genetic correlation between IA and ASAH, and liability to drug usage independent of the risk factor high blood pressure. Next, we evaluated the causality and therapeutic potential of independent correlated drug classes using three different Mendelian randomization frameworks. Results Blood pressure-independent correlations with IA were found for antidepressants, paracetamol, acetylsalicylic acid, opioids, beta-blockers, and peptic ulcer and gastro-oesophageal reflux disease drugs. MR showed that the genetically predicted usage of none of these drug classes were causally related to IA. Genetically predicted high responders to antidepressant drugs were at higher risk of IA (odds ratio [OR]=1.61, 95% confidence interval (CI)=1.09-2.39, P=0.018) and ASAH (OR=1.68, 95%CI=1.07-2.65, P=0.024) if they used antidepressant drugs. This effect was absent in non-users. For beta-blockers, additional analyses showed that this effect was not independent of blood pressure after all. Genetic liability to chronic multisite pain, an indication for pain medication (paracetamol, acetylsalicylic acid, and opioids), was associated with increased IA risk (OR=1.63, 95%CI=1.24-2.14), but not consistently across sensitivity analyses. Conclusions We did not find drugs decreasing liability to IA and ASAH but did find that antidepressant drugs may increase liability. In addition, we observed pleiotropy between IA, chronic pain, and pain medication usage, but the driving factor for this pleiotropy remains to be determined. Our results help to better understanding pathogenic mechanisms underlying IA.