Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Abstract

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics.

Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients.

Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10^-3 per year [95% CI, -6.49×10^-3 to -3.14×10^-3]; P=1.82×10^-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041).

Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Keywords: aneurysmal subarachnoid hemorrhage; genetic heterogeneity; genetics; intracranial aneurysm; risk assessment.

Figure 1.

Overview of constructing the metaGRS. A, Steps to create the metaGRS used for prediction in the HUNT (Nordic HUNT study). B, Steps to create intracranial aneurysm (IA) GWAS summary statistics to be included in an adjusted metaGRS version for phenotype-genotype correlation analysis. Single IA GWAS strata were excluded from the IA GWAS in a leave-one-out manner prior to the “Best model selection” step in A. AAA indicates abdominal aortic aneurysm; Age Mnp, age at menopause; Age Mrch, age at menarche; BMI, body mass index; CPD, cigarettes per day; DBP, diastolic blood pressure; DPW, alcoholic drinks per week; EPI (focal), focal epilepsy; EPI (gen), generalized epilepsy; FMD (any), any fibromuscular dysplasia; HDL, high-density lipoprotein; HUNT, Nordic HUNT study; ICH (deep), deep intracerebral hemorrhage; IS (any), any ischemic stroke; LDL, low-density lipoprotein; mFMD, multifocal fibromuscular dysplasia; MIG (any), any migraine; N births, number of births; SBP, systolic blood pressure; sCEU, stratum of mixed European ancestry; sFC, French Canada; sFIN, Finnish; sFRA, France; sNL1; sNL2, Netherlands; sPOL, Poland; sUK1; sUK2, United Kingdom; sUSA, United States of America; T2D, type II diabetes; TC, total cholesterol; TG, triglycerides; Vert AD, vertebral artery dissection; WHR, waist-to-hip ratio; and YoE, years of education.

Figure 2.

Prediction of aneurysmal subarachnoid hemorrhage (ASAH) using the metaGRS in the HUNT study. C-index according to different combinations of clinical risk factors and metaGRS are shown. Error bars denote 95% CIs. HR: hazard ratio per SD-specified genetic risk score (GRS). Reference: model including only sex. Clinical: model including sex, intracranial aneurysm (IA), systolic blood pressure, and smoking.

Figure 3.

Association of metaGRS with patient characteristics. The metaGRS was transformed to mean 0, variance 1. A, metaGRS according to single or multiple intracranial aneurysms (IAs). Horizontal lines correspond to population mean (middle line), and mean±one population SD. B, Effect of age at aneurysmal subarachnoid hemorrhage (ASAH) on metaGRS. Line denotes regression line, with shared area being the 95% CI. C, Effect of having an IA at the internal carotid artery (ICA) versus other locations, on the metaGRS.