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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

Quantile‐quantile (QQ) plots of IA, AAA, and TAA GWAS and the aneurysm mega‐analysis. A, Dutch IA GWAS; (B) Finnish IA GWAS; (C) AAA GWAS; (D) TAA GWAS; (E) aneurysm mega‐analysis. These QQ plots show the observed distribution of P values (black dots) plotted against the expected distribution of P values (blue line) on a negative log10 scale, for each of the 4 GWAS (Dutch IA and Finnish IA, AAA, and TAA) and for all cohorts combined in the aneurysm mega‐analysis. Genomic inflation factors (λGC) per study, defined as the ratio of the median of the empirically observed distribution of the test statistic to the expected median, are also shown. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; TAA, thoracic aortic aneurysm.
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jah31537-fig-0003: Quantile‐quantile (QQ) plots of IA, AAA, and TAA GWAS and the aneurysm mega‐analysis. A, Dutch IA GWAS; (B) Finnish IA GWAS; (C) AAA GWAS; (D) TAA GWAS; (E) aneurysm mega‐analysis. These QQ plots show the observed distribution of P values (black dots) plotted against the expected distribution of P values (blue line) on a negative log10 scale, for each of the 4 GWAS (Dutch IA and Finnish IA, AAA, and TAA) and for all cohorts combined in the aneurysm mega‐analysis. Genomic inflation factors (λGC) per study, defined as the ratio of the median of the empirically observed distribution of the test statistic to the expected median, are also shown. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; TAA, thoracic aortic aneurysm.

Mentions: Table 2 shows the numbers of cases, controls, and SNPs of all 4 cohorts after QC and imputation. Quantile‐quantile (QQ) plots for each GWAS per cohort are shown in Figure 3.


Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms
Quantile‐quantile (QQ) plots of IA, AAA, and TAA GWAS and the aneurysm mega‐analysis. A, Dutch IA GWAS; (B) Finnish IA GWAS; (C) AAA GWAS; (D) TAA GWAS; (E) aneurysm mega‐analysis. These QQ plots show the observed distribution of P values (black dots) plotted against the expected distribution of P values (blue line) on a negative log10 scale, for each of the 4 GWAS (Dutch IA and Finnish IA, AAA, and TAA) and for all cohorts combined in the aneurysm mega‐analysis. Genomic inflation factors (λGC) per study, defined as the ratio of the median of the empirically observed distribution of the test statistic to the expected median, are also shown. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; TAA, thoracic aortic aneurysm.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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

jah31537-fig-0003: Quantile‐quantile (QQ) plots of IA, AAA, and TAA GWAS and the aneurysm mega‐analysis. A, Dutch IA GWAS; (B) Finnish IA GWAS; (C) AAA GWAS; (D) TAA GWAS; (E) aneurysm mega‐analysis. These QQ plots show the observed distribution of P values (black dots) plotted against the expected distribution of P values (blue line) on a negative log10 scale, for each of the 4 GWAS (Dutch IA and Finnish IA, AAA, and TAA) and for all cohorts combined in the aneurysm mega‐analysis. Genomic inflation factors (λGC) per study, defined as the ratio of the median of the empirically observed distribution of the test statistic to the expected median, are also shown. AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; TAA, thoracic aortic aneurysm.
Mentions: Table 2 shows the numbers of cases, controls, and SNPs of all 4 cohorts after QC and imputation. Quantile‐quantile (QQ) plots for each GWAS per cohort are shown in Figure 3.

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