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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.


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Polygenic analysis results. (A) AAA‐associated SNPs tested for association with TAA case‐control status; (B) TAA‐associated SNPs tested for association with AAA case‐control status; (C) IA‐associated SNPs tested for association with TAA case‐control status; (D) TAA‐associated SNPs tested for association with IA case‐control status; (E) IA‐associated SNPs tested for association with AAA case‐control status; (F) AAA‐associated SNPs tested for association with IA case‐control status. We created polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs at different P value thresholds and tested these scores for association to case‐control status in GWAS cohorts of IA, AAA, and TAA in each possible combination between these phenotypes. The figures show the resulting P values of the association tests (left y‐axis) for each polygenic model (x‐axis), with the corresponding number of SNPs in each model (right y‐axis). AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.
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jah31537-fig-0006: Polygenic analysis results. (A) AAA‐associated SNPs tested for association with TAA case‐control status; (B) TAA‐associated SNPs tested for association with AAA case‐control status; (C) IA‐associated SNPs tested for association with TAA case‐control status; (D) TAA‐associated SNPs tested for association with IA case‐control status; (E) IA‐associated SNPs tested for association with AAA case‐control status; (F) AAA‐associated SNPs tested for association with IA case‐control status. We created polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs at different P value thresholds and tested these scores for association to case‐control status in GWAS cohorts of IA, AAA, and TAA in each possible combination between these phenotypes. The figures show the resulting P values of the association tests (left y‐axis) for each polygenic model (x‐axis), with the corresponding number of SNPs in each model (right y‐axis). AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.

Mentions: Next, we investigated whether groups of SNPs associated with 1 type of aneurysm (eg, IA) were also associated with the other types (eg, AAA or TAA). The results of these polygenic analyses with the IA, AAA, and TAA GWAS cohorts are shown in Tables 3, 4, 5, 6, 7 through 8 and in Figure 6. No SNP sets with a significant joint effect on another aneurysm type were observed, except for a small group of 7 SNPs associated with IA with P<10−6. This SNP set was associated with AAA with P=5×10−3 (Table 7). When taking a closer look at this SNP set, it appears that the polygenic association is driven by 2 SNPs (rs36071109 at 2q33; PAAA=2.3×10−3; and rs4330012 at 18q11; P (cursive)AAA= 1.3×10−2), both in very strong LD to genome‐wide significant SNPs in our mega‐analysis described above. (The pleiotropic 9p21 locus shared by IA and AAA had already been adjusted for.)


Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms
Polygenic analysis results. (A) AAA‐associated SNPs tested for association with TAA case‐control status; (B) TAA‐associated SNPs tested for association with AAA case‐control status; (C) IA‐associated SNPs tested for association with TAA case‐control status; (D) TAA‐associated SNPs tested for association with IA case‐control status; (E) IA‐associated SNPs tested for association with AAA case‐control status; (F) AAA‐associated SNPs tested for association with IA case‐control status. We created polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs at different P value thresholds and tested these scores for association to case‐control status in GWAS cohorts of IA, AAA, and TAA in each possible combination between these phenotypes. The figures show the resulting P values of the association tests (left y‐axis) for each polygenic model (x‐axis), with the corresponding number of SNPs in each model (right y‐axis). AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.
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jah31537-fig-0006: Polygenic analysis results. (A) AAA‐associated SNPs tested for association with TAA case‐control status; (B) TAA‐associated SNPs tested for association with AAA case‐control status; (C) IA‐associated SNPs tested for association with TAA case‐control status; (D) TAA‐associated SNPs tested for association with IA case‐control status; (E) IA‐associated SNPs tested for association with AAA case‐control status; (F) AAA‐associated SNPs tested for association with IA case‐control status. We created polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs at different P value thresholds and tested these scores for association to case‐control status in GWAS cohorts of IA, AAA, and TAA in each possible combination between these phenotypes. The figures show the resulting P values of the association tests (left y‐axis) for each polygenic model (x‐axis), with the corresponding number of SNPs in each model (right y‐axis). AAA indicates abdominal aortic aneurysm; GWAS, genome‐wide association study; IA, intracranial aneurysm; SNP, single‐nucleotide polymorphism; TAA, thoracic aortic aneurysm.
Mentions: Next, we investigated whether groups of SNPs associated with 1 type of aneurysm (eg, IA) were also associated with the other types (eg, AAA or TAA). The results of these polygenic analyses with the IA, AAA, and TAA GWAS cohorts are shown in Tables 3, 4, 5, 6, 7 through 8 and in Figure 6. No SNP sets with a significant joint effect on another aneurysm type were observed, except for a small group of 7 SNPs associated with IA with P<10−6. This SNP set was associated with AAA with P=5×10−3 (Table 7). When taking a closer look at this SNP set, it appears that the polygenic association is driven by 2 SNPs (rs36071109 at 2q33; PAAA=2.3×10−3; and rs4330012 at 18q11; P (cursive)AAA= 1.3×10−2), both in very strong LD to genome‐wide significant SNPs in our mega‐analysis described above. (The pleiotropic 9p21 locus shared by IA and AAA had already been adjusted for.)

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