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

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Manhattan plot of the aneurysm GWAS mega‐analysis. This Manhattan plot shows the P values of all SNPs with an association with P<10−4 to disease (IA, AAA, or TAA). P values on the y‐axis are presented on an inverse log scale. The x‐axis represents the genomic position of each SNP. The red horizontal line represents P=5×10−8, the cut‐off value for genome‐wide association. Index SNPs with P<1×10−6 are depicted as diamonds, whereas SNPs in the same LD block as these SNPs are depicted as yellow and red dots. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; LD, linkage disequilibrium; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.
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jah31537-fig-0004: Manhattan plot of the aneurysm GWAS mega‐analysis. This Manhattan plot shows the P values of all SNPs with an association with P<10−4 to disease (IA, AAA, or TAA). P values on the y‐axis are presented on an inverse log scale. The x‐axis represents the genomic position of each SNP. The red horizontal line represents P=5×10−8, the cut‐off value for genome‐wide association. Index SNPs with P<1×10−6 are depicted as diamonds, whereas SNPs in the same LD block as these SNPs are depicted as yellow and red dots. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; LD, linkage disequilibrium; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.

Mentions: In total, 3094 cases, 9507 controls, and 9 245 988 SNPs were available for the mega‐analysis across all 4 aneurysm cohorts (λGC=1.06). The results of this mega‐analysis are shown in a Manhattan plot (Figure 4). We found 4 genome‐wide significant loci, though all these loci were previously described as risk loci for IA, AAA, and/or TAA. The direction of effect for these loci was consistent across all four aneurysm cohorts (see forest plots in Figure 5). First, SNPs at the known IA and AAA risk locus 9p21 near CDKN2A, CDKN2B, and CDKN2BAS were associated.11, 18 The strongest association at this locus was found for rs7866503, with P=2.1×10−13. The second association was found for SNPs at the known IA risk locus 18q11 near RBBP8,11 with the strongest association for rs8087799 (P=1.6×10−9). The third association was found for SNPs at the known TAA risk locus 15q21 near FBN1,17 with the strongest association for rs595222 (P=1.0×10−8). The fourth association was found for rs919433 (P=4.6×10−8), which is located at 2q33 near ANKRD44. The same SNP was previously found to be associated with IA in a Finnish and Dutch population.24 This SNP is also in strong LD (r2=0.7) with a nearby SNP (rs700651), which was previously found to be associated with IA in a Dutch, Finnish, and Japanese population,12 but did not reach genome‐wide significance after adding other populations of IA patients.11


Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms
Manhattan plot of the aneurysm GWAS mega‐analysis. This Manhattan plot shows the P values of all SNPs with an association with P<10−4 to disease (IA, AAA, or TAA). P values on the y‐axis are presented on an inverse log scale. The x‐axis represents the genomic position of each SNP. The red horizontal line represents P=5×10−8, the cut‐off value for genome‐wide association. Index SNPs with P<1×10−6 are depicted as diamonds, whereas SNPs in the same LD block as these SNPs are depicted as yellow and red dots. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; LD, linkage disequilibrium; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015357&req=5

jah31537-fig-0004: Manhattan plot of the aneurysm GWAS mega‐analysis. This Manhattan plot shows the P values of all SNPs with an association with P<10−4 to disease (IA, AAA, or TAA). P values on the y‐axis are presented on an inverse log scale. The x‐axis represents the genomic position of each SNP. The red horizontal line represents P=5×10−8, the cut‐off value for genome‐wide association. Index SNPs with P<1×10−6 are depicted as diamonds, whereas SNPs in the same LD block as these SNPs are depicted as yellow and red dots. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; LD, linkage disequilibrium; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.
Mentions: In total, 3094 cases, 9507 controls, and 9 245 988 SNPs were available for the mega‐analysis across all 4 aneurysm cohorts (λGC=1.06). The results of this mega‐analysis are shown in a Manhattan plot (Figure 4). We found 4 genome‐wide significant loci, though all these loci were previously described as risk loci for IA, AAA, and/or TAA. The direction of effect for these loci was consistent across all four aneurysm cohorts (see forest plots in Figure 5). First, SNPs at the known IA and AAA risk locus 9p21 near CDKN2A, CDKN2B, and CDKN2BAS were associated.11, 18 The strongest association at this locus was found for rs7866503, with P=2.1×10−13. The second association was found for SNPs at the known IA risk locus 18q11 near RBBP8,11 with the strongest association for rs8087799 (P=1.6×10−9). The third association was found for SNPs at the known TAA risk locus 15q21 near FBN1,17 with the strongest association for rs595222 (P=1.0×10−8). The fourth association was found for rs919433 (P=4.6×10−8), which is located at 2q33 near ANKRD44. The same SNP was previously found to be associated with IA in a Finnish and Dutch population.24 This SNP is also in strong LD (r2=0.7) with a nearby SNP (rs700651), which was previously found to be associated with IA in a Dutch, Finnish, and Japanese population,12 but did not reach genome‐wide significance after adding other populations of IA patients.11

View Article: PubMed Central - PubMed

ABSTRACT

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&#8208;occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs.

Methods and results: We performed a mega&#8208;analysis of 1000 Genomes Project&#8208;imputed genome&#8208;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&#8208;, AAA&#8208;, and TAA&#8208;associated SNPs and tested these scores for association to case&#8208;control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium&ndash;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&#8208;nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16&nbsp;843 controls (IA) and 4391 cases and 37&nbsp;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&times;10&minus;5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1&times;10&minus;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.

No MeSH data available.


Related in: MedlinePlus