Genetic risk score for intracranial aneurysms to predict aneurysmal subarachnoid hemorrhage and identify associations with patient characteristics

Background Rupture of an intracranial aneurysm (IA) causes aneurysmal subarachnoid hemorrhage (ASAH). There is no accurate prediction model for IA or ASAH in the general population. Recent discoveries in genetic risk for IA may allow improved risk prediction. Methods We constructed a genetic risk score including genetic association data for IA and 17 traits related to IA (a metaGRS) to predict ASAH incidence and IA presence. The metaGRS was trained in 1,161 IA cases and 407,392 controls in the UK Biobank and validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68,568 controls from the Nordic HUNT study. We further assessed association between genetic risk load and patient characteristics in a cohort of 5,560 IA patients. Results The hazard ratio for ASAH incidence was 1.34 (95% confidence interval = 1.20-1.51) per SD increase of metaGRS. Concordance index increased from 0.63 [0.59-0.67] to 0.65 [0.62-0.69] upon including the metaGRS on top of clinical risk factors. The odds ratio for prediction of IA presence was 1.09 [95% confidence interval: 1.01-1.18], but did not improve area under the curve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10−3 per year [-6.49×10−3 to -3.14×10−3], P=1.82×10−8), and location at the internal carotid artery (OR=0.92 [0.86 to 0.98], P=0.0041). Conclusions The metaGRS was predictive of ASAH incidence with modest added value over clinical risk factors. Genetic risk plays a role in clinical heterogeneity of IA. Additional studies are needed to identify the biological mechanisms underlying this heterogeneity. What is already known on this topic Recent advanced in the understanding of genetic risk for IA opened and opportunity for risk prediction by combining genetic and conventional risk factors. What this study adds Here, we developed a genetic risk score based on genetic association information for IA and 17 related traits. This risk score improved prediction compared to a model including only conventional risk factors. Further, genetic risk was associated with age at ASAH and IA location. How this study might affect research, practice, or policy This study emphasizes the importance of combining conventional and genetic risk factors in prediction of IA. It provides a metric to develop an accurate risk assessment method including conventional and genetic risk factors. ### Competing Interest Statement JHV reports to have sponsored research agreements with Biogen. ### Funding Statement We acknowledge the support from the Netherlands Cardiovascular Research Initiative: An initiative with support of the Dutch Heart Foundation, CVON2015-08 ERASE. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 852173). The project was funded in part by NIH grant R35HL161016 and University of Michigan Taubman Institute. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Biobanks Review Committee of the University Medical Center Utrecht on June 25th 2013 gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online here: (including UK Biobank for all samples, male only, and female only) and here: (excluding UK Biobank for all samples, male only, and female only). Data can be used and shared upon citation of this paper and adapted if the contributions are distributed under the same conditions.