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

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Intracranial aneurysms ( <jats:styled-content style="fixed-case">IAs</jats:styled-content> ), abdominal aortic aneurysms ( <jats:styled-content style="fixed-case">AAAs</jats:styled-content> ), and thoracic aortic aneurysms ( <jats:styled-content style="fixed-case">TAAs</jats:styled-content> ) 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 <jats:styled-content style="fixed-case">IAs</jats:styled-content> , <jats:styled-content style="fixed-case">AAAs,</jats:styled-content> and <jats:styled-content style="fixed-case">TAAs</jats:styled-content> . </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( <jats:styled-content style="fixed-case">GWAS</jats:styled-content> ) data of 4 previously published aneurysm cohorts: 2 <jats:styled-content style="fixed-case">IA</jats:styled-content> cohorts (in total 1516 cases, 4305 controls), 1 <jats:styled-content style="fixed-case">AAA</jats:styled-content> cohort (818 cases, 3004 controls), and 1 <jats:styled-content style="fixed-case">TAA</jats:styled-content> cohort (760 cases, 2212 controls), and observed associations of 4 known <jats:styled-content style="fixed-case">IA</jats:styled-content> , <jats:styled-content style="fixed-case">AAA</jats:styled-content> , and/or <jats:styled-content style="fixed-case">TAA</jats:styled-content> risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on <jats:styled-content style="fixed-case">IA</jats:styled-content> ‐, <jats:styled-content style="fixed-case">AAA</jats:styled-content> ‐, and <jats:styled-content style="fixed-case">TAA</jats:styled-content> ‐associated <jats:styled-content style="fixed-case">SNP</jats:styled-content> s 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 ( <jats:styled-content style="fixed-case">IA</jats:styled-content> ) and 4391 cases and 37 904 controls ( <jats:styled-content style="fixed-case">AAA</jats:styled-content> ), and found nominally significant associations for <jats:styled-content style="fixed-case">IA</jats:styled-content> risk locus 18q11 near <jats:italic> <jats:styled-content style="fixed-case">RBBP</jats:styled-content> 8 </jats:italic> to <jats:styled-content style="fixed-case">AAA</jats:styled-content> (odds ratio [ <jats:styled-content style="fixed-case">OR</jats:styled-content> ]=1.11; <jats:italic>P</jats:italic> =4.1×10 <jats:sup>−5</jats:sup> ) and for <jats:styled-content style="fixed-case">TAA</jats:styled-content> risk locus 15q21 near <jats:italic> <jats:styled-content style="fixed-case">FBN</jats:styled-content> 1 </jats:italic> to <jats:styled-content style="fixed-case">AAA</jats:styled-content> ( <jats:styled-content style="fixed-case">OR</jats:styled-content> =1.07; <jats:italic>P</jats:italic> =1.1×10 <jats:sup>−3</jats:sup> ). </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> Although there was no evidence for polygenic overlap between <jats:styled-content style="fixed-case">IAs</jats:styled-content> , <jats:styled-content styl ...