Dissecting the Genetic Architecture of Intracranial Aneurysms

Background The genetic risk of intracranial aneurysm (IA) development has been ascribed largely to the genetic risk of smoking exposure and hypertension. However, the relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear. Methods We performed a genome-wide association study in the Million Veteran Program testing association of roughly 25 million DNA variants with unruptured IA (3,165 cases and 592,927 controls) in veterans of European, African, and Hispanic ancestries. This was meta-analyzed with publicly available summary statistics to yield a final cohort of 15,438 cases and 1,183,973 controls. Candidate causal genes were prioritized through expression quantitative trait loci colocalization, fine-mapping transcriptome wide association studies, and multi-trait colocalization. We constructed a cerebrovascular single nucleus RNA sequencing (snRNA-seq) dataset and integrated IA summary statistics to prioritize candidate causal cell types. We then constructed a polygenic risk score to identify patients at greater risk of developing IA. Results We identified five novel loci association with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 16 candidate causal genes. Amongst other cardiovascular traits, we found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm, and we identified 13 IA risk loci that colocalize with aneurysmal, atherosclerotic, and blood pressure traits. Integration of an IA gene set with human cerebrovascular snRNA-seq data revealed significant association with matrix-producing pericytes, smooth muscle cells (SMCs), and other mural subtypes. In addition, gene expression analysis revealed enrichment of several candidate genes within SMCs and pericytes. Finally, a high polygenic risk score (PRS) was significantly associated with IA across European (OR: 1.87, CI: 1.61-2.17, P = 8.8 × 10−17), African (OR: 1.62, CI: 1.19-2.15, P = 1.2 × 10−3), and Hispanic (OR: 2.28, CI: 1.47-3.38, P = 1.0 × 10−4) ancestries. Conclusion Here, we identify five novel loci associated with IA. Integration of summary statistics with cerebrovascular snRNA-seq reveals association of cell-types involved in matrix production. We constructed and validated a PRS that predicts IA, while controlling for demographic variables including smoking status, sex, and blood pressure. Taken together, our findings suggest that an intrinsic deficit in matrix production and vascular integrity may drive IA pathogenesis independent of systemic hypertension and smoking exposure. ### Competing Interest Statement P.N. reports grants from Amgen, Apple, AstraZeneca, Boston Scientic, and Novartis, is a consultant for Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, geneXwell, Novartis, Roche / Genentech, and TenSixteen Bio, is a scientific co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. Derek Klarin is a senior scientific advisor for and accepts consulting fees from Bitterroot Bio, unrelated to the present work. ### Funding Statement This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards # I01- BX003362 (P.S.T. and K.-M.C.)/K2-CX001780 (S.M.D.)/IK2BX005759-01 (D.K), and the VA Informatics and Computing Infrastructure (VINCI) VA HSR RES 130457 (J.A.L.). SSA is supported by the NIH T32HL 98049-13. NJL is supported by the NIH R35HL 144475 and AHA EIA34770065. DK is additionally supported by AHA 23SCEFIA1153369. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The VA Central Institutional Review Board and Million Veteran Program Proposal and Publication Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The full summary level association data from the MVP IA discovery analysis and meta-analysis from this manuscript will be available through dbGAP, accession code phs00167.v2.p1 upon publication.