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Review Article
Originally Published 17 August 2021
Free Access

Genetics of Intracranial Aneurysms

Mark K. Bakker, MSc https://orcid.org/0000-0002-7887-9014, and Ynte M. Ruigrok, MD, PhD https://orcid.org/0000-0002-5396-2989 [email protected]Author Info & Affiliations
Stroke
Volume 52, Number 9
https://doi.org/10.1161/STROKEAHA.120.032621
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Abstract

Rupture of an intracranial aneurysm leads to aneurysmal subarachnoid hemorrhage, a severe type of stroke which is, in part, driven by genetic variation. In the past 10 years, genetic studies of IA have boosted the number of known genetic risk factors and improved our understanding of the disease. In this review, we provide an overview of the current status of the field and highlight the latest findings of family based, sequencing, and genome-wide association studies. We further describe opportunities of genetic analyses for understanding, prevention, and treatment of the disease.
See related articles, p 2974, p 2983, p 2992, p 3013, p 3025
Aneurysmal subarachnoid hemorrhage (ASAH) is a type of stroke caused by rupture of an intracranial aneurysm (IA). It occurs in relatively young people; the mean age is 50 years.1 Although ASAH is relatively rare constituting only 5% of all strokes,1 it has a major impact due to its devastating effects: one-third of patients dies and one-third remains dependent on help.2 In contrast to the relatively low ASAH incidence, unruptured IA (UIA) are common with a 3% prevalence in the general population.3 These UIA often remain undiagnosed until they rupture. ASAH and UIA are one of the few cardiovascular diseases occurring more often in women than men with two-third of patients being women.3,4
A twin-based study estimated the heritability of ASAH at ≈40%,5 indicative of an important genetic component in the pathogenesis of UIA and ASAH. The heritability is driven by both rare, penetrant mutations as well as common variants with small effect sizes. All common variants combined can currently explain 21% to 29% of the disease,6 whereas the total contribution of rare variants is unknown. Well-established clinical risk factors for both UIA and ASAH are hypertension and smoking.7,8
In this review, we summarize the latest discoveries in the genetics of UIA and ASAH. We discuss Mendelian monogenic disorders with IA as one of their clinical manifestations and the discovery of common, low-frequency and rare genetic variants associated with IA. We also review efforts to translate the findings of these genetic studies to underlying biological mechanisms and discuss how genetic discoveries could help to improve diagnosis, risk prediction, and treatment of patients at high risk for or diagnosed with IA in the future.

Sporadic Versus Familial IAs

First-degree relatives of ASAH patients have an increased risk of ASAH compared with the general population, and 10% of ASAH patients have relatives who also had an ASAH.9 In a population-based study, the odds ratio of ASAH for persons with one affected first-degree relative was 2.15 (95% CI, 1.77–2.59) compared with sporadic cases, while for persons with 2 affected first-degree relatives the odds ratio increased to 51.0 (95% CI, 8.56–1117).10 UIA are also more common in patients with a positive family history.3 Preventive screening for UIA using magnetic resonance angiography has proven to be cost effective in first-degree relatives of ASAH patients.11–13 ASAH can subsequently be prevented by endovascular or surgical treatment of the UIA identified with magnetic resonance angiography. Patients with a positive family history (familial cases) more often have ruptured IA of the middle cerebral artery (while sporadic cases usually have these at the anterior communicating artery), have ASAH at a younger age and are more likely to have multiple IA than patients without such a family history (sporadic cases).14

Monogenic Disorders Associated With IAs

Monogenic disorders are caused by penetrant mutations of a single gene, typically displaying Mendelian inheritance patterns. Several monogenic conditions are associated with IA, including autosomal dominant polycystic kidney disease,15 type IV Ehlers-Danlos syndrome (vascular subtype),16,17 Marfan syndrome,16,18 Loeys Dietz syndrome,16,19 and Majewski Osteodysplastic Primordial Dwarfism, Type II (Table 1).20–23 As most of the monogenic conditions predisposing to IA are rare, the case series in which UIA and ASAH in these disorders are described are small. Therefore, precise estimates of the occurrence of UIA and ASAH in these disorders are not possible. It is not known to what extent these specific heritable disorders contribute to the entire population of IA patients but they are thought to account only for a very small proportion. Only for autosomal dominant polycystic kidney disease, the condition associated with IA with the highest prevalence in the general population, that is, 1/1000 individuals,24 such an estimate can be made and this disease only accounts for 1.2% of all IA patients.25
Table 1. Monogenic Disorders Associated With Intracranial Aneurysms
DiseaseGenes implicatedEvidence for IA predisposition
Autosomal dominant polycystic kidney diseasePKD1, PKD210% of patients have UIA.15
Type IV Ehlers-Danlos syndrome (vascular subtype)COL3A1In 12 of 99 (12%) patients screened UIA were found.16 Patients (n=9000 more often admitted because of an IA than controls (n=9000; 0.4% vs 0.09%; P<0.01).17
Marfan SyndromeFBN1In 8 of 59 (14%) patients screened UIA were found.16 Patients compared with controls (both groups n=13 883) more likely to have ASAH and hemorrhagic stroke (0.3% vs 0.2%) and UIA (0.2% vs 0.1%).18
Loeys Dietz syndromeTGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3In 7 of 25 (28%) patients screened UIA were found.16 Cerebral hemorrhage (ASAH and intracerebral hemorrhage) in 2 of 90 (7%) patients.
Microcephalic/Majewski’s Osteodysplastic Primordial Dwarfism, Type IIPCNTUIA in up to 50% of patients20–23
ASAH indicates aneurysmal subarachnoid hemorrhage; IA, intracranial aneurysm; and UIA, unruptured intracranial aneurysm.

Genetic Studies of IAs

In this review, we focus on genetic studies including markers across the whole genome and briefly mention candidate gene studies. We distinguish 3 types: (1) genome-wide association studies (GWAS), aimed at discovering common variants typically with small effect size; (2) low-frequency variant association studies in high-risk populations using a similar case/control design as GWAS; and (3) family based studies for the discovery of rare variants with large effect size. These include linkage analysis to discover segregating regions of DNA and next-generation sequencing to narrow-down potential causal variants. An overview of all identified genetic loci in these studies is show in the Figure.
Figure. Overview of all risk loci for intracranial aneurysm (IA). Blue bars depict regions found in linkage studies. Red diamonds are genes found in whole-exome sequencing studies or burden analysis (Table 3). Text labels correspond to these gene names. Blue dots are lead single-nucleotide polymorphisms or copy number variants identified in genome-wide association studies (Table 2).
Table 2. Genome-Wide Association Studies of Intracranial Aneurysms
YearPopulationCasesControlsLead SNPLocusAnnotated geneRisk alleleOdds ratio95% CI
2008Dutch, Finnish, Japanese2620756952rs7006512q33.1PLCL1G1.241.15–1.34
rs109584098q11.23SOX17A1.361.24–1.49
rs92985068q11.23SOX17A1.351.22–1.49
rs13330409p21.3CDKN2A-CDKN2BT1.291.19–1.40
2010Finnish, mixed European, Japanese27589114181rs92985068q11.23SOX17A1.281.20–1.38
rs13330409p21.3CDKN2A-CDKN2BT1.321.25–1.39
rs1241340910q24.32CNNM2G1.291.19–1.40
rs931520413q13.1STARD13-KLT1.201.13–1.28
rs1166154218q11.2RBBP8C1.221.15–1.28
2010Japanese331027853No genome-wide significant findings
2010Japanese34191282No genome-wide significant findings
2011Finnish, mixed European, Japanese30589114181rs68415814q31.22EDNRAG1.221.14–1.31
2012Japanese31243112696rs68422414q31.22EDNRAC1.251.16–1.34
2012European ancestry2814831683rs64756069p21.3CDKN2B-AS1T1.35Not reported
2014Finnish and Dutch2923359565rs749727142q23.3LYPD6C1.89Not reported
rs124723552q33.1ANKRD44A1.27Not reported
rs1138162165q31.3FSTL4G1.66Not reported
rs750182136q24.2EPM2AA1.87Not reported
rs13330429p21.3CDKN2B-AS1A1.31Not reported
2014Mixed European ancestry, Dutch and Finnish3241337869rs102302077p21.1HDAC9T1.211.14–1.28
rs107333769p21.3CDKN2B-AS1NA1.341.23–1.45
2015Portuguese35200499No genome-wide significant findings
2018French-Canadian362571992rs15546003p14.2FHITC3.862.46–6.07
2018Japanese371765742No genome-wide significant findings
2019Korean38250294No genome-wide significant findings*
2020Mixed European, Finnish, Dutch, British, Japanese, Chinese, French-Canadian, Polish610754306882rs68415814q31.22EDNRAA0.800.77–0.84
rs47059385q31.1SLC22A5/SLC22A4/P4HA2T1.131.09–1.17
rs111530716q16.1FHL5A1.161.11–1.22
rs625165508q11.23SOX17T1.171.12–1.22
rs15373739p21.3CDKN2B-AS1T0.840.81–0.86
rs1118783810q23.33PLCE1A0.920.89–0.94
rs73299810q24.33NT5C2/MARCKSL1P1T1.191.14–1.25
rs228054311p15.5BET1LT1.271.19–1.35
rs1104499112p12.2RP11-664H17.1A0.880.84–0.92
rs268149212q21.33ATP2B1T1.121.08–1.17
rs713773112q22FGD6/NR2C1T0.890.86–0.92
rs374232113q13.1STARD13T0.870.84–0.90
rs803419115q25.1PSMA4T0.890.85–0.93
rs718452516q23.1BCAR1/RP11-252K23.2A1.151.11–1.19
rs1166154218q11.2RBBP8A0.870.85–0.90
rs481486320p11.23SLC24A3A1.111.07–1.15
rs3971322q12.2MTMR3T1.201.12–1.28
All SNPs that passed the genome-wide significance threshold of P<5×10−8 are reported. The number of cases and controls reported are the numbers used to the reported association statistics. These typically are a meta-analysis of discovery and replication cohort. Annotated gene column shows gene names reported in the original publications. If not described, we reported the nearest gene. LD indicates linkage disequilibrium; and SNP, single-nucleotide polymorphism.
*
In the study by Hong et al38 many SNPs reached P<5×10−8, but all loci consisted of single SNPs and no replication was done. Therefore, no SNPs are shown there. rs10958409 and rs9298506 are not in LD. rs9298506 and rs62516550 are in moderate LD (r2=0.21 in Europeans), but not with rs10958409. rs113816216 and rs4705938 are not in LD.
Table 3. Genes Identified in Whole-Exome Sequencing Studies of Intracranial Aneurysms
GeneNPopulationLocusLead mutationEvidenceAdditional mutationsGene function
ADAMTS154212/42Japanese11q24.2p.E133Q, c.397G>C (NM_139055.2), rs185269810Segregated in 1 familyNot investigatedA disintegrin and metalloproteinase with thrombospondin motif.
Found in 3 other families.
Replicated in 24 additional familial cases, not in 426 sporadic cases.
Silencing of ADAMTS15 increased endothelial cell migration.
RNF213436/26French-Canadian17q25.3MultipleEnriched burden of protein-altering variants in familial cases.rs6565666Suggested in vascular wall construction.
The protein contains an ATPase associated with diverse cellular Activities (AAA) domain with E3 ubiquitin ligase activity.
Found a SNP in this gene in a replication cohort of 257 cases and 1988 controls (odds ratio=1.45, P=7.8×10−4).
Associated with other vascular diseases.44–46
THSD1471/9European ancestry13q14.3p.R450X, c.1348C>T (NM_018676.3), NAIn a linkage locus (13q14.12-21.1).41p.L5FExpressed in endothelial cells of cerebral arteries.
Variant fully segregated in 9 cases and 13 controlsp.R460W
p.E466GPlays a role in vascular development in zebrafish and mice.48
Thsd1 loss-of-function caused cerebral hemorrhage in zebrafish and subarachnoid hemorrhage in mice.p.G600E
p.P639L
p.T653I
p.S775P
ANGPTL6491/4French19p13.2p.K460X, c.1378A>T (NM_031917.2), rs769022609Selected from 8 variants that were carried by all affected family members.p.E131VCirculating pro-angiogenic factor.
p.L348FStimulates endothelial cell migration and endothelial permeability.
p.A153VfsX66
A statistically significant burden of rare (MAF<1%), nonsynonymous variants in this gene was found in 95 index cases vs 404 controls (P=0.023). 
Mutated (p.K460X) ANGPTL6 was nearly undetectable in culture medium of HEK293T cell lines, while being expressed in similar amounts as wild-type ANGPTL6.
Serum levels of ANGPTL6 reduced 50% in p.K460X carriers.
LOXL2501/4Chinese8p21.3p.H45Y, c.133C>T (NM_002318.3), rs142252012This variant was selected based on gene functions from 15 novel SNVs and 3 rare (MAF<1%) indels that were shared by all affected family members.Not investigatedThe LOX family is involved in crosslink formation in collagens and in elastin, providing strength and elasticity to vascular walls.
ARHGEF17519/20Chinese11q13.4p.A1465D, c.4394C>A (NM_014786.4), rs22988086 variants in 6 genes segregated in at least 2 families of the discovery cohort, and also found in at least 1 of 86 replication cases. Only ARHGEF17 showed increased burden of rare damaging variants in all cases combined.p.R1723QActivates Rho GTPases, thereby promoting formation of actin stress fibers that play a role in cell shape, polarity, migration, cell-cell and cell-matrix interactions.
p.C1776Y
Previous studies highlighted ARHGEF17 as a candidate gene for intracranial aneurysms.
PCNT523/13European ancestry21q22.3p.R2728C, c.8182C>T (NM_006031.6), rs7628904082 genes found with rare (MAF<1%), damaging variants segregating within all cases and controls in 2 families. PCNT was selected because of its role in MOPD-II.NoneCentrosome assembly and microtubule formation throughout the cell cycle.
Binds intracranial aneurysm risk protein PKD2. Risk gene for MOPD-II.
p.V2811L, c.8431 G>T (NM_006031.6), rs144757781
NFX1531/7Chinese9p13.3p.L840P, c.2518T>C (NM_002504.6), NAThe only variant found in 7 affected family members and absent in 7 unaffected.Not investigatedUnknown gene function.
Not implicated in cerebrovascular disease before.
Found in 1 unaffected family member (29 y old).
The mutation column shows the identified gene mutation (amino acid change, nucleotide change, and SNP ID if available). If applicable, the mutation column shows the lead gene variant identified in the discovery phase of the reported study. Pedigrees/cases show the number of pedigrees included in the study, as reported in the publication, and the number of cases among all studied pedigrees. LOX indicates lysyl oxidase; MAF, minor allele frequency; MOPD-II, Majewski Osteodysplastic Primordial Dwarfism, Type II; N, number of pedigrees/number of cases; PKD2, polycystic kidney disease 2; SNP, single-nucleotide polymorphism; and SNV, single-nucleotide variant.

Common Genetic Variants

Thus far, 6 large (defined as >2000 cases) GWAS on IA were published.6,26–32 Currently, 19 risk loci were identified in these studies combined: 2q33.1, 4q31.22, 5q31.1, 6q16.1, 7p21.1, 8q11.23, 9p21.3, 10q23.33, 10q24.33, 11p15.5, 12p12.2, 12q21.33, 12q22, 13q13.1, 15q25.1, 16q23.1, 18q11.2, 20p11.23, and 22q12.2 (Figure, Table 2). Risk loci 2q33.1, 8q11.23 (consisting of 2 signals), and 9p21.3 were the first found to be associated with IA in a study of 2075 cases and 6952 controls.26 These have been replicated in subsequent studies,6,27–29 although the 2q33.1 locus (genetic region harboring an unknown causal variant) was not found in the largest ones.6,27,30 Three risk loci 10q24.32, 13q13.1, and 18q11.2 were found after supplementing the first study to 5891 cases and 14 181 controls.27 Applying a more liberal posterior probability of association on the same dataset revealed another risk locus: 4q31.22.30 These loci were replicated in later studies.6,31 A GWAS initiated by the Familial IA study on 2617 cases and 2548 controls discovered an additional risk locus on chromosome 7p21.1,32 which is not yet replicated in other studies. Recently, a meta-analysis including nearly all samples from previous GWAS of IA, and multiple additional cohorts, totaling 10 754 cases and 306 882 controls was conducted.6 Here, all but 2 loci (2q33.1 and 7p21.1) were replicated, and 11 new loci were found: 5q31.1, 6q16.1, 10q23.33, 11p15.5, 12p12.2, 12q21.33, 12q22, 15q25.1, 16q23.1, 20p11.23, and 22q12.2.
Several smaller GWAS (including <2000 cases) were conducted,28,33–38 which resulted in the finding of one associated risk variant on locus 3p14.2,36 which was not found in other GWAS, and replication of the already known loci 4q31.22 and 9p21.3.28,31
In addition to these GWAS, common variants were studied in several candidate gene studies. In a meta-analysis, 6 variants showed an association with IA: rs42524 (COL1A2), rs1800255 (COL3A1), rs251124 and rs173686 (SERPIN3A), and rs3767137 (HSPG2).39 None of these variants have been confirmed in GWAS so far.

Low-Frequency Genetic Variants

Two studies investigated the association of low-frequency variants (minor allele frequency <5%) with IA.29,40 In a study in a Finnish population isolate of 1615 cases and 6563 controls variants associated with IA were found on chromosomes 2q23.3, 5q31.3, and 6q24.2. The latter 2 loci replicated in 717 Dutch cases and 3004 controls.29 Another Dutch study on 995 cases and 2080 controls focusing on protein-coding variants identified FBLN2 (3p25.1) using a gene-based approach to increase statistical power.40 This association was not replicated in a European ancestry cohort of 425 cases and 311 controls, but the strength of association increased in a combined analysis.40

Rare Genetic Variants

The first efforts to find Mendelian risk genes for IA used linkage analysis and were reviewed before.41 The identified loci (logarithm of odds >2) are 1p34.3-36.13, 2p13-15, 4q32.2-3, 5p15.2-14.3, 5q22-31, 7q11, 8p22.2, 11q24-25, 12p12.3, 13q14.12-21.1, 14q22-31, 17cen, 19q13.11-13.3, and Xp22.41 As next-generation sequencing, particularly whole-exome sequencing (WES), became available, it was possible to identify rare (typically minor allele frequency <1%) variants that segregated within families, rather than large genomic segments from linkage analysis. This provided 8 potential Mendelian risk genes: LOXL2 (chr8), NFX1 (chr9), ARHGEF17 (chr11), ADAMTS15 (chr11), THSD1 (chr13), RNF213 (chr17), ANGPTL6 (chr19), and PCNT (chr21; Table 3). The evidence varies per gene. For ADAMTS15,42 THSD1,47 ANGPTL6,49 and ARHGEF17,51 functional experiments support their roles in IA. For PCNT,52 it was already known that mutations cause Majewski Osteodysplastic Primordial Dwarfism, Type II which predisposes to IA (Table 1). Rare coding mutations in LOXL250 and NFX153 segregated in families with IA, but more evidence to support the involvement of these genes in IA is needed. The mutational burden in RNF21343 was higher in IA cases, indicating that mutations in this gene are risk factors rather than causal variants. RNF213 is also implicated in other cerebrovascular diseases, being Moya Moya disease,44 fibromuscular dysplasia,45 and intracranial artery stenosis.46 Three other WES studies did not result in the identification of risk genes for IA.54–56
None of the variants identified in family studies have been found in other populations. Additional rare, damaging, variants in ANGPTL657 and low-frequency variants in PCNT, RNF213, and THSD1 were identified in other populations,58 but evidence for causality of these additional variants is limited. Therefore, it is yet unknown if these genes have a wide clinical relevance in UIA and ASAH.

Translating GWAS to Biological Mechanisms

One of the main aims of GWAS is to understand the biological mechanisms underlying development and rupture of IA. Below, we summarize the current understanding of biological mechanisms in IA based on GWAS findings.

Mapping GWAS Loci to Genes

In recent years, several tools were developed to link loci to genes using expression quantitative trait loci (the effect of genetic variants on gene expression of a particular gene) data. In the latest GWAS, expression quantitative trait locus analysis led to the selection of 11 potential causative genes: SLC22A5, SLC22A4, P4HA2, SOX17, NT5C2, MARCKSL1P1, FGD6, NR2C1, PSMA4, BCAR1, and RP11-252K23.2.6 FGD6 and SOX17 are involved in vascular endothelial cell signaling,59,60 suggesting an important role for this cell type in IA. BCAR1 encodes a mechanical stress sensor and may contribute to UIA development or rupture through vascular pressure sensing.61

Mapping GWAS Loci to Biological Mechanisms

Gene-mapping methods allow gene-set enrichment analysis, but no gene set with a sufficient number of associated genes has been described for IA. Instead, advances in heritability enrichment analysis allow pathway, gene-set and cell-type enrichment directly on summary statistics, without a candidate gene set. In the most recent GWAS, such analyses showed that genomic regulatory regions were enriched, similar to other polygenic diseases.6 This is in line with earlier findings that IA-associated single-nucleotide polymorphisms (SNPs) were enriched in regulatory regions of the arteries in the Circle of Willis.62 Moreover, regions surrounding genes that are specifically expressed in endothelial and mural cells (the layer of smooth muscle cells and pericytes) were enriched, supporting findings from an epigenetic study that regulatory regions near IA-associated SNPs were especially active in endothelial cells.63

Genetic Overlap With Other Diseases

Studying similarities in genetic causes (known as genetic overlap) with other diseases can help understand the pathogenesis of a disease. In the largest GWAS of IA to date, genetic correlation (ρg) was observed with ischemic stroke (ρg=19.5±7.9% [SE]), deep intracerebral hemorrhage (ρg=51.6±19.8%) and abdominal aortic aneurysms (ρg=30.2±10.5%).6 Conditioning IA GWAS results on GWAS for blood pressure (BP) and smoking pack years (similar to including BP and smoking as a covariate in a GWAS), showed that the correlation between IA and ischemic stroke was driven by BP and smoking, while the correlation between IA and deep intracerebral hemorrhage was driven, in part, by BP and smoking and probably involves additional shared mechanisms. Finally, the correlation between IA and abdominal aortic aneurysms was explained by smoking but not by BP.

Potential Clinical Applications

Several efforts have been made to use genetic knowledge to find biomarkers for risk prediction and candidates for therapy of the disease.

Risk Prediction

Genetic risk score (GRS), combining risk-associated common genetic variants, can be used to predict risk of complex diseases.64 So far, few GRS studies in IA have been performed and these used relatively small sample sizes and ≤10 SNPs to construct the GRS.
In the first GRS study of IA, a GRS using 7 risk SNPs was not associated with aneurysm size at the time of rupture in 955 Dutch ASAH cases.65 Later, this study was supplemented with 718 Finnish IA cases, and it was shown that individuals with a higher GRS were more likely to develop an IA on the middle cerebral artery compared with all other arterial locations (odds ratio [95% CI], 1.54 [1.20–1.98] for highest versus lowest tertile).66 In another study, identifying 120 IAs in 4890 individuals from a population cohort, GRS for IA (using 10 SNPs) was associated with aneurysm volume and diameter.67
Recently, the explained heritability of IA increased substantially from 5%30 to 21.6±2.8% or 29.9±5.4% using linkage equilibrium score regression and linkage disequilibrium adjusted kinship, respectively.6 This means that the explained heritability is over half of the total heritability (40%),5 potentially allowing better risk prediction for IA. Future studies will show if GRS indeed have predictive value for IA and if clinical implementation of GRS may be useful.

Discovering Causal Risk Factors Using Genetic Data

Most disease risk factors have a (small) genetic predisposition. Mendelian randomization (MR) mimics the effect of a randomized trial for an exposure (such as BP) on an outcome trait (such as IA), using randomly allocated genetic predisposition for the exposure. This allows assessment of the causal effect that the exposure has on the outcome. An early MR study, including 717 Dutch cases and 1988 controls, did not find MR effects on IA for type 2 diabetes, body mass index, or waist-to-hip ratio adjusted body mass index.68 MR analysis of traits measured in the UK Biobank showed causal effects of BP and smoking on IA risk.6 It was already known that hypertension and smoking are important clinical risk factors for IA,7,8 but this MR analysis further underlines the causal involvement of these risk factors from a genetic perspective. An MR study of genetically determined protein levels found that Scavenger receptor class A, member 5 (SCARA5; a ferritin receptor that mediates nontransferrin-dependent delivery of iron) was protective of ASAH and cardioembolic stroke.69 No predicted MR effect of SCARA5 on any other disease was found and SCARA5 could, therefore, be a promising biomarker for ASAH.

Therapeutic Targets

Data-driven approaches combining GWAS data with drug bioactivity data can identify drug classes that target genes associated with a disease and consequently can aid in finding strategies for drug repurposing. Drug targets with human genetic evidence are more likely to lead to approved drugs.70 Enrichment of GWAS effects in genes targeted by existing drugs in IA showed that antiepileptic drugs and sex hormones have pleiotropic effects on IA (area under the receiver operating characteristic curve =0.675 and 0.652, respectively).6 A limitation of this approach is that the direction of effect cannot be established. Further genetic and epidemiological studies on shared risk of IA, epilepsy, and sex hormone levels are required to determine whether antiepileptic drugs or sex hormone-related drugs have therapeutic value in preventing IA development and rupture.

Conclusions

Genetics of IA is an active field in which many discoveries were made in recent years. Family based studies expanded the number of genes and mutations proven to cause familial IA, while GWASs, especially those performed in large collaborative efforts, have identified 17 independent and replicated loci across the genome with an effect on IA risk. These genetic studies in IA can help understand the causes and biology of IA and identify targets for therapeutic intervention. Important genetic roles for BP and smoking have been proven and vascular endothelial cells have been suggested as drivers of the disease. It was also shown that genes targeted by antiepileptic drugs and sex hormones are enriched in the largest GWAS performed to date. Sex hormone drug target enrichment is in line with the high prevalence in women but the role of antiepileptic drugs in IA prevention needs to be investigated further. These findings could provide therapeutic targets for IA.
Findings of WES and GWAS studies can be used in risk prediction. WES assumes penetrant, Mendelian variants that have a high chance of causing a disease. The IA risk genes discovered in WES studies were identified in varying populations. Whether these genes play a role in other populations and whether routine genetic screening is beneficial in individuals at risk, such as family members of ASAH patients, has to be investigated.
GWAS studies assume small effect sizes in common genetic variants. Recent advances in GWAS showed a substantial explained heritability for IA showing an important role for common genetic variants. This opens the possibility for a GRS to detect patients at high risk of UIA development who could be followed up for preventive screening. Prediction by GRS can be improved by combining multiple GRSs of risk factors into one meta-score (metaGRS), which was shown effective for ischemic stroke prediction.71 It should be noted that most studies of IA genetics were performed in the White European population, some in persons from Asian ancestry, and none in, for example, persons from African descent. This could lead to a biased understanding of the disease and even worse to refrainment of treatment options derived from genetic findings in ethnic minorities.
In recent years, discoveries in genetics of IA have accelerated. Still, we are only beginning to understand IA genetics. As study sizes and bioinformatic possibilities increase, detailed phenotypes, such as aneurysm location and shape, and disease progression, can be accurately investigated. These advances, as well as large international collaborations will likely further accelerate genetic discoveries in IA.

Acknowledgments

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 programme (PRYSM; grant agreement No. 852173).

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Go to Stroke
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Stroke
Volume 52 • Number 9 • September 2021
Pages: 3004 - 3012
PubMed: 34399582

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© 2021 American Heart Association, Inc.

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Published online: 17 August 2021
Published in print: September 2021

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Keywords

  1. genetics
  2. humans
  3. intracranial aneurysm
  4. risk factors
  5. subarachnoid hemorrhage

Subjects

  1. Aneurysm
  2. Cerebral Aneurysm
  3. Cerebrovascular Disease/Stroke
  4. Genetic, Association Studies
  5. Genetics

Authors

Affiliations

Mark K. Bakker, MSc https://orcid.org/0000-0002-7887-9014
University Medical Center Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, the Netherlands.
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Ynte M. Ruigrok, MD, PhD https://orcid.org/0000-0002-5396-2989 [email protected]
University Medical Center Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, the Netherlands.
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Notes

For Sources of Funding and Disclosures, see page 3011.
Correspondence to: Ynte M. Ruigrok, MD PhD, UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Room G03-228, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Email [email protected]

Disclosures

Disclosures None.

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None.

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Genetics of Intracranial Aneurysms
Stroke
  • Vol. 52
  • No. 9

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  • Vol. 52
  • No. 9
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