Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort

Abstract

Background: Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.

Methods and results: In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ~10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA.

Conclusions: Our GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.

Fig 1. Top SNPs associated with AAA.

(A) Manhattan plot of GWAS results (MAF >0.5%) for AAA. Significance is displayed on the y-axis as -log₁₀ of the p-value, with results ordered along the x-axis by chromosome (each bar represents a different chromosome). (B-G) Prevalence of abdominal aortic aneurism (AAA) per 100,000 participants in the UK Biobank by genotype. Bars labeled with ratio of cases: Controls. (B) Prevalence of AAA decreases with ADAMTS8 variant rs7936928 status (P-value = 7.51x10^-9, OR per T allele = 0.786). Decrease in AAA prevalence is noted in the homozygotes for the minor allele (T/T) in comparison to the heterozygotes (C/T) and the noncarriers (C/C) in a stepwise, “dosage-dependent” manner. (C) Prevalence of AAA increases with JAK2 variant rs193181528 status (P-value = 3.26x10^-8, OR per C allele = 2.776). (D) Prevalence of AAA increases with ATOH8 variant rs113626898 status (P-value = 9.06x10^-9, OR per A allele = 2.714). (E) Prevalence of AAA increases with LINC01021 variant rs116390453 status (P-value = 4.26 x10^-9, OR per T allele = 2.505). (F) Prevalence of AAA decreases with CDKN2B-AS1 variant rs1537373 status (P-value = 6.68x10^-7, OR per T allele = 0.8211). (G) Prevalence of AAA decreases with CELSR2 variant rs12740374 status (P-value = 2.04x10^-7, OR per T allele = 0.7668).

Fig 2. Top SNPs associated with TAA.

(A) Manhattan plot of GWAS results (MAF >0.5%) for TAA. (B-D) Prevalence of thoracic aortic aneurism (AAA) per 100,000 participants in the UK Biobank by genotype. Bars labeled with ratio of cases: Controls. (B) Prevalence of TAA increases with CTNNA3 variant rs149014140 status (P-value = 1.82x10^-8, OR per G allele = 4.268). (C) Prevalence of TAA increases with FRMD6 variant rs148927240 status (P-value = 2.19x10^-8, OR per A allele = 4.23). (D) Prevalence of TAA increases with MPB variant rs78851735 status (P-value = 3.79x10^-8, OR per T allele = 3.446).

Fig 3. Prevalence of TAA increases with FBN1 variant rs1561207 status and bradycardia.

(A) Increase in TAA prevalence per 100,000 participants in the UK Biobank is noted in the homozygotes for the minor allele (T/T) in comparison to the heterozygotes (C/T) and the noncarriers (C/C) in a pronounced stepwise, “dosage-dependent” manner (P-value = 1.57x10^-6, OR per T allele 1.615). Bars labeled with ratio of cases: Controls. (B) Prevalence of TAA rises with bradycardia (purple, heart rate ≤ 54 beats per minute, bpm) in a stepwise manner from tachycardia (orange, defined as heart rate ≥ 91 bpm, OR = 1.89) to normal rate (green, heart rate 55 to 90 bpm, OR = 1.62) to bradycardia (purple, heart rate ≤ 54 bpm, OR = 2.09). P-value = 0.01622 by Pearson’s Chi-squared test. (C) This relationship is seen in both FBN1 variant carriers (GT) and noncarriers (GG), but the impact of bradycardia is more dramatic in homozygous variant carriers (TT).