Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
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DOI：
10.1371/journal.pone.0247287
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Hong CC
中科院分区：
文献类型：
--
作者：
Ashvetiya T;Fan SX;Chen YJ;Williams CH;O'Connell JR;Perry JA;Hong CC
众所周知，胸主动脉瘤（TAA）和腹主动脉瘤（AAA）具有很强的遗传成分。在一项使用英国生物银行的全基因组关联研究（GWAS）中，我们分析了1363名AAA患者的基因组，与27,260名年龄、血统和性别匹配的对照组（1:20病例：对照研究设计）进行了比较。对435名TAA患者和8700名对照组进行了类似的分析。小等位基因频率（MAF）为0.0.5%。除了三个已知的基因座外，我们还在LINC01021、ATOH8和JAK2基因附近发现了新的基因座，这些基因座对AAA具有全基因组意义（p值<5 × 10-8）。对于TAA， CTNNA3、FRMD6和MBP中的三个新位点具有全基因组意义。与AAAs和TAAs相关的基因没有重叠。此外，我们还发现了一个高频变异连锁组（MAFs ~10%），其中包括马凡综合征的致病基因FBN1，该基因与TAA相关。在FinnGen PheWeb中，这种FBN1单倍型与主动脉夹层相关。最后，我们发现基线心动过缓与TAA相关，而与AAA无关。我们的GWAS发现AAA和TAA与不同的基因组相关，表明不同的潜在遗传结构。我们还发现基线心动过缓与TAA之间存在关联。这些发现，包括JAK2关联，提供了合理的机制和治疗见解。我们还发现，在没有马凡氏综合征的患者中，常见的FBN1连锁组与TAA和主动脉夹层相关。这些FBN1变异提示马凡病和散发性TAA之间存在共同的病理生理机制。
Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component. 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. 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.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
3.5
作者：
Sakai LY;Keene DR;Renard M;De Backer J
通讯作者：
De Backer J
腹主动脉瘤的全基因组关联研究的荟萃分析确定了四个新的疾病特异性风险基因座。
影响因子：
20.1
作者：
Jones GT;Tromp G;Kuivaniemi H;Gretarsdottir S;Baas AF;Giusti B;Strauss E;Van't Hof FN;Webb TR;Erdman R;Ritchie MD;Elmore JR;Verma A;Pendergrass S;Kullo IJ;Ye Z;Peissig PL;Gottesman O;Verma SS;Malinowski J;Rasmussen-Torvik LJ;Borthwick KM;Smelser DT;Crosslin DR;de Andrade M;Ryer EJ;McCarty CA;Böttinger EP;Pacheco JA;Crawford DC;Carrell DS;Gerhard GS;Franklin DP;Carey DJ;Phillips VL;Williams MJ;Wei W;Blair R;Hill AA;Vasudevan TM;Lewis DR;Thomson IA;Krysa J;Hill GB;Roake J;Merriman TR;Oszkinis G;Galora S;Saracini C;Abbate R;Pulli R;Pratesi C;Saratzis A;Verissimo AR;Bumpstead S;Badger SA;Clough RE;Cockerill G;Hafez H;Scott DJ;Futers TS;Romaine SP;Bridge K;Griffin KJ;Bailey MA;Smith A;Thompson MM;van Bockxmeer FM;Matthiasson SE;Thorleifsson G;Thorsteinsdottir U;Blankensteijn JD;Teijink JA;Wijmenga C;de Graaf J;Kiemeney LA;Lindholt JS;Hughes A;Bradley DT;Stirrups K;Golledge J;Norman PE;Powell JT;Humphries SE;Hamby SE;Goodall AH;Nelson CP;Sakalihasan N;Courtois A;Ferrell RE;Eriksson P;Folkersen L;Franco-Cereceda A;Eicher JD;Johnson AD;Betsholtz C;Ruusalepp A;Franzén O;Schadt EE;Björkegren JL;Lipovich L;Drolet AM;Verhoeven EL;Zeebregts CJ;Geelkerken RH;van Sambeek MR;van Sterkenburg SM;de Vries JP;Stefansson K;Thompson JR;de Bakker PI;Deloukas P;Sayers RD;Harrison SC;van Rij AM;Samani NJ;Bown MJ
通讯作者：
Bown MJ
影响因子：
30.8
作者：
Gould RA;Aziz H;Woods CE;Seman-Senderos MA;Sparks E;Preuss C;Wünnemann F;Bedja D;Moats CR;McClymont SA;Rose R;Sobreira N;Ling H;MacCarrick G;Kumar AA;Luyckx I;Cannaerts E;Verstraeten A;Björk HM;Lehsau AC;Jaskula-Ranga V;Lauridsen H;Shah AA;Bennett CL;Ellinor PT;Lin H;Isselbacher EM;Lino Cardenas CL;Butcher JT;Hughes GC;Lindsay ME;Baylor-Hopkins Center for Mendelian Genomics;MIBAVA Leducq Consortium;Mertens L;Franco-Cereceda A;Verhagen JMA;Wessels M;Mohamed SA;Eriksson P;Mital S;Van Laer L;Loeys BL;Andelfinger G;McCallion AS;Dietz HC
通讯作者：
Dietz HC
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ