Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results: We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication

Genetic risk load according to the site of intracranial aneurysms

We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size-weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10(-4)), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10(-5)). GRS were not associated with familial IA in the Dutch (p = 0.34), Finnish (p = 0.45), and combined cohort (p = 0.98), or with age at time of IA rupture in the Dutch (p = 0.28), Finnish (p = 0.86), and combined cohort (p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67-1.20) for familial IA, 1.03 (0.79-1.34) for lower age, and 1.54 (1.20-1.98) for MCA aneurysms. Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studie

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects similar to 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment(1). The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm(2-5). Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells(6-8), suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role(9). These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm

Five loci with a genome-wide significant association to saccular intracranial aneurysm (sIA) disease in the Finnish and Dutch samples.

*<p>For each variant minor allele/major allele, locus and base pair position are given.</p>**<p>The variant's distance (kb) to the nearest gene is given.</p>***<p>Located in the intron of the given gene.</p>†<p>The previously reported 9p21.3 locus <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004134#pgen.1004134-Yasuno2" target="_blank">[12]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004134#pgen.1004134-Helgadottir1" target="_blank">[39]</a>.</p>‡<p>The previously studied 2q33.3 locus with inconclusive evidence (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004134#s4" target="_blank">Materials and Methods</a>).</p>§<p>Some heterogeneity in effect sizes exists between cohorts. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004134#pgen.1004134.s015" target="_blank">Table S9</a> for heterogeneity statistics.</p

Regional association plots of the five identified saccular intracranial aneurysm (sIA) loci in the combined Finnish samples and the Dutch sample.

<p>Association p-values (−log10 scale, y-axis) of variants are shown according to their chromosomal positions (x-axis). Blue lines indicate the genetic recombination rate (cM/Mb). Figures A–C present the loci identified in the case vs. control analysis at 2q23.3, 5q31.3, and 6q24.2, respectively. Figure D presents the 7p22.1 locus associated to the sIA count per patient. Figure E presents the 2q33.1 locus with inconclusive previous evidence. Purple rectangles indicate the most significant variant in a) the Finnish discovery sample and, along the dashed line, its p-values in b) the combined Finnish samples (META FIN) and in c) all samples (META ALL). Adjacent variants in linkage disequilibrium (r²; EUR populations, 1000 Genomes March 2012) to the index variant are shown in colours indicating their r² levels (r² box in each figure).</p

The Finnish and Dutch study samples used in the association analysis of saccular intracranial aneurysm (sIA) disease.

*<p>Unknown familial sIA status for 35 patients.</p>**<p>Number of sIAs not known for 16 patients.</p><p>SD = Standard deviation.</p

The locus with a genome-wide significant association to the number of saccular intracranial aneurysms (sIA) per individual in the Finnish samples.

*<p>For each variant major allele/minor allele, locus and base pair position are given.</p>**<p>Located in the intron of the given gene.</p>§<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004134#pgen.1004134.s015" target="_blank">Table S9</a> for heterogeneity statistics.</p

Study design.

<p>The Finnish discovery and replication cohorts represent a population with over two-fold increased risk of subarachnoid hemorrhage from ruptured saccular intracranial aneurysm (sIA-SAH). The Finnish discovery cohort was intentionally enriched with familial sIA patients, and 9.4M genotyped and imputed variants were studied. The loci with p<5E-6 were replicated in an independent and unselected Finnish sIA sample. The allele frequencies and effect sizes of the replicated variants in Finland were finally compared to continental European population using a Dutch sample. The sIA-SAH risk is not increased in the Netherlands (‘general risk’ in the figure).</p

Author Correction: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Correction to: Nature Genetics https://doi.org/10.1038/s41588-020-00725-7, published online 16 November 2020