Genetic Determinants of Unruptured Intracranial Aneurysms in the General Population
Background and Purpose—Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for intracranial aneurysms in clinical samples. In addition, SNPs have been discovered for blood pressure, one of the strongest risk factors for intracranial aneurysms. We studied the role of these genetic variants on occurrence and size of unruptured intracranial aneurysms, discovered incidentally in a general community-dwelling population.
Methods—In 4890 asymptomatic participants from the Rotterdam Study, 120 intracranial aneurysms were identified on brain imaging and segmented for maximum diameter and volume. Genetic risk scores (GRS) were calculated for intracranial aneurysms (10 SNPs), systolic blood pressure (33 SNPs), and diastolic blood pressure (41 SNPs).
Results—The GRS for intracranial aneurysms was not statistically significantly associated with presence of aneurysms in this population (OR, 1.16; 95% CI, 0.96–1.40; P=0.119), but showed a significant association with both maximum diameter (difference in log-transformed mm per SD increase of GRS, 0.10; 95% CI, 0.02–0.19; P=0.018) and volume (difference in log-transformed µL per SD increase of GRS, 0.21; 95% CI, 0.01–0.41; P=0.040) of aneurysms. GRSs for blood pressures were associated with neither presence nor size of aneurysms.
Conclusions—Genetic variants previously identified for intracranial aneurysms in clinical studies relate to the size rather than the presence of incidentally discovered, unruptured intracranial aneurysms in the general population.
Unruptured intracranial aneurysms are incidentally discovered in imaging studies in ≈2% of the general population.1 Rupture of an intracranial aneurysm can result in a nontraumatic subarachnoid hemorrhage (SAH), an acute condition with high morbidity and mortality rates. For early risk stratification and potential treatment, it is, therefore, important to better understand the pathophysiology of aneurysm development.
Several risk factors for ruptured intracranial aneurysms have been identified, including age, sex, smoking, aneurysm size, and location.2–4 In addition, an important modifiable risk factor for ruptured intracranial aneurysms is hypertension.5 Less is known about risk factors for development of intracranial aneurysms, although there is some overlap with risk factors for rupture, including sex, smoking, and hypertension.6,7 Genetic factors also play an important role in intracranial aneurysms, which is evidenced by the fact that persons with a positive family history have a higher risk of developing intracranial aneurysms compared with the general population.8 More recently, genome-wide association studies have identified multiple single-nucleotide polymorphisms (SNPs) associated with intracranial aneurysms.9 Importantly, most studies investigating genetics of intracranial aneurysms have done so in a clinical setting, thereby typically including patients presenting with ruptured aneurysms or persons screened for high familial risk. In such settings, it cannot be discerned whether these SNPs affect the development of intracranial aneurysms or lead to growth and rupture of already present aneurysms. A population-based setting provides a unique opportunity to study the effect of these SNPs on unselected unruptured aneurysms.
We investigated in a community-dwelling population the association of SNPs for intracranial aneurysms with the occurrence and size of unruptured aneurysms, incidentally detected on research imaging. Furthermore, we also studied SNPs for high blood pressure and their association with presence and size of unruptured intracranial aneurysms.
Methods are available in the online-only Data Supplement.
Setting and Study Population
This study was embedded in the prospective Rotterdam Study,10 a population-based cohort study in the Netherlands. Between 2005 and 2014, 5832 unique persons have undergone magnetic resonance imaging of the brain.11 The study cohort was genotyped across the whole genome, with genotype data available for 4890 of 5832 subjects.
Assessment and Measurement of Intracranial Aneurysms on Magnetic Resonance Imaging
Reported incidental findings by research physicians were reassessed by a neuroradiologist and categorized accordingly. None of the participants had a history of SAH. Detected intracranial aneurysms were manually segmented. A three-dimensional model of the aneurysm was reconstructed, enabling us to calculate maximum diameter and volume of saccular intracranial aneurysms.
Construction of the Genetic Risk Score
Because of the small effects of individual SNPs and the relatively small number of aneurysms in our population-based setting, we constructed a genetic risk score (GRS) to leverage the cumulative effect of all SNPs, allowing us to achieve higher power. For primary analyses, we restricted to SNPs reaching a genome-wide significance (P<5×10–8) in white populations, but in secondary analyses we included SNPs from non-white populations. The extracted SNP data are described in Table I in the online-only Data Supplement.
We used logistic regression to associate GRSs with presence of intracranial aneurysms (yes/no). Among persons with aneurysms, we used linear regression to associate GRSs with size of saccular intracranial aneurysms. Size was defined in both maximum diameter (mm) and volume (µL). For subjects with multiple saccular aneurysms, we calculated total aneurysm size by summing up the size of all the saccular aneurysms. In all analyses, we adjusted for age, sex, and additionally for smoking status, systolic blood pressure, diastolic blood pressure, and use of blood pressure–lowering medication (antihypertensives, diuretics, β-blocking agents, calcium channel blockers, and angiotensin-converting enzyme inhibitors). Because persons could have multiple saccular aneurysms, hence greatly determining total aneurysm size, we also adjusted for number of aneurysms when performing analyses for size.
In 4890 magnetic resonance imaging scans, we found 120 aneurysms in 109 unique persons (2%), with 10 persons having multiple aneurysms (maximum 3 per person). The persons with intracranial aneurysms had a mean age of 65.4±11.9 years and 73 (67.0%) were women. Of the 120 aneurysms, 114 (95%) were located in the anterior circulation and 113 (94.2%) were saccular with a median (interquartile range) maximum diameter of 5.5 mm (range, 4.3–7.4) and volume of 52.8 μL (range, 27.6–125.6). The 4781 persons without aneurysms had a mean age of 65.2±10.9 years and 2610 (54.6%) were women. Study characteristics are described in Table 1.
We did not find any significant associations between GRSs and presence of intracranial aneurysms (Table 2).
In contrast, the GRS for intracranial aneurysms showed a significant age- and sex-adjusted association with maximum diameter (difference in log-transformed mm per SD increase of GRS, 0.10; 95% CI, 0.02–0.18; P=0.018) and volume (difference in log-transformed µL per SD increase of GRS, 0.21; 95% CI, 0.01–0.41; P=0.040) of saccular aneurysms. The association remained statistically significant after additional adjustment (Table 3). Creating a GRS by including SNPs identified in non-white populations yielded slightly attenuated, but still statistically significant results (Tables II and III in the online-only Data Supplement). Individual analyses for each SNP of the risk score are shown in Table IV in the online-only Data Supplement. Two SNPs (rs1333040 and rs6475606) showed nominal significance with intracranial aneurysm size, but did not survive Bonferroni correction. Results for alternative methods of calculating aneurysm size are shown in Table V in the online-only Data Supplement.
No significant associations were found for the GRSs of systolic blood pressure and diastolic blood pressure.
In this study of community-dwelling persons, genetic risk variants for intracranial aneurysms were not associated with presence of unruptured, incidentally discovered intracranial aneurysms. However, these genetic variants in combination were found to relate to larger size of incidental saccular aneurysms. Genetic risk variants for blood pressure were associated with neither presence nor size of intracranial aneurysms.
A major strength of our study is, that we obtained unruptured intracranial aneurysms in a population-based setting, allowing us to investigate the association between genetic risk factors and intracranial aneurysm presence in truly asymptomatic individuals. Another strength is the manual segmentation of the entire aneurysm, enabling us to calculate saccular aneurysm volume instead of only the diameter, thus representing actual aneurysm size more accurately. A limitation of our study is the relatively old age of participants. Although aneurysmal SAH incidence increases with age,12 a substantial portion of patients presenting with SAH are young adults. Because of the high morbidity and mortality associated with rupture of aneurysms, these patients were probably not included in our cohort of elderly persons. Combined with the limited statistical power considering a total of 109 cases, this could also explain why we did not find a statistically significant association for presence of aneurysms. Furthermore, the incidental aneurysms in this study were typically small (median volume=52.8 μL), which could make measurements inaccurate. However, inter-rater agreement was excellent for both the maximum diameter and volume, indicating that the estimated aneurysm size was reliable. Also, intracranial aneurysms are more prevalent in persons with rare genetic diseases such as Loeys–Dietz syndrome and polycystic kidney disease. Even though information about the occurrence of these diseases was not available in our population, we expect the influence to be minimal in our cohort of healthy persons.
Most genetic variants for aneurysms have been identified using cases from a clinical setting, that is, patients with rupture of intracranial aneurysms. In such a setting, it cannot be discerned whether these genetic variants affect the development of intracranial aneurysms or lead to growth and rupture of already present aneurysms. In our community-dwelling population, we did not find a statistically significant association between these genetic variants and the presence of incidental intracranial aneurysms, although the confidence interval for the odds ratio included values that would indicate a potentially important association (OR as large as 1.40). The absence of a statistically significant association may thus reflect low statistical power. Interestingly, despite the small numbers of persons with aneurysms, we did find an association between these genetic variants combined and the size of intracranial aneurysms, which is one of the strongest risk factors for rupture.13 In addition, large aneurysms also have an increased risk of further enlargement.14 Taken together, our findings suggest that SNPs previously associated with intracranial aneurysms in a clinical setting are probably associated with the aneurysm size in the general population and thus, potentially with their subsequent rupture.
A previous study in patients presenting with SAH did not find any association between similar genetic variants and diameter of aneurysms at the time of rupture,15 using 7 of the 10 SNPs we used. Possible explanations for the difference in results between studies are the difference in study population, and the fact that aneurysm rupture may potentially affect the observed aneurysm size.
Further research could explore the predictive ability of GRSs, identifying additional SNPs to enhance discrimination and rupture risk classification in persons with intracranial aneurysms. We specifically created GRSs for blood pressure genes because hypertension is one of the strongest modifiable risk factors associated with aneurysm rupture. However, smoking and heavy alcohol consumption, among other risk factors, are also strongly associated with aneurysm formation and rupture,5 and future research should focus on these as well.
We demonstrated that genetic risk variants identified for intracranial aneurysms from a clinical setting were not associated with aneurysm presence in the general population. However, we did show that these genetic risk variants affect aneurysm size, known to be one of the strongest risk factors for rupture. This possibly suggests that the clinically identified SNPs are mainly associated with aneurysm rupture, rather than with the presence of aneurysms in a general population.
Sources of Funding
The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek), The Netherlands Organization for Health Research and Development (Zorgonderzoek Nederland/Medische Wetenschappen), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (Directorates General XII), and the Municipality of Rotterdam.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.010414/-/DC1.
- Received June 11, 2015.
- Revision received July 17, 2015.
- Accepted July 22, 2015.
- © 2015 American Heart Association, Inc.
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