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.

Performance of a diagnostic model for the presence of unruptured intracranial aneurysms in the general population

“…Moreover, previous research also has shown that the added value of genetic over clinical data for aSAH and UIAs is limited. 32 Our study has some limitations. First, the Rotterdam Study assessed presence of UIAs on protondensity T2-weighted brain MRI scans, instead of on MRA with which UIAs are best detected.…”

Novel Polygenic Risk Score for Intracranial Aneurysms

“…The predictive value of the metaGRS remains limited, given that it did not improve prediction of IA presence above a model including clinical risk factors. One reason for this could be the presence of undetected and unruptured IAs in the control group, as suggested by the authors, 8 which would attenuate the statistical power to predict IAs. Only an improved characterization of the controls via brain vessel imaging (eg, MRA, CTA) can resolve this issue.…”

“…Among the 17 selected traits are established IA risk factors, such as blood pressure and smoking, and diseases genetically correlated with IA, including ischemic stroke. 8 To construct the score, the authors utilized an "elastic net regression" methodology in a training sample from the UK Biobank (1161 IA cases, 407 392 controls). In this way, a total of 7 078 955 SNPs were included in the score.…”

“…Despite these limitations, the novel PRS by Bakker et al 8 is a major improvement over previous scores. The statistical power is considerably larger, as the utilized genome-wide association study more than doubled the number of cases compared to previous studies (7495 IA/ASAH cases, 71 934 controls).…”

“…In this issue of Stroke , Bakker et al 8 address this gap by creating a novel genetic risk score of IA. The authors leverage a recent genome-wide association study of IA and aneurysmal subarachnoid hemorrhage (ASAH) 9 along with association data of 17 IA-related traits, to create a “meta Genetic Risk Score” (metaGRS).…”