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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

Abstract

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.

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Fig. 1: AsAoD view, distribution by ancestry and Manhattan plot GWAS among individuals of European ancestry.
Fig. 2: Gene–tissue enrichment.
Fig. 3: Association between PGS for AsAoD and aortic diseases.
Fig. 4: PheWAS of PGS for AsAoD.
Fig. 5: Forest plot depicting casual effect estimate for blood pressure and lipid biomarkers.

Data availability

All imaging and genetic data of the UK Biobank are available upon request to the UK Biobank organization. Summary statistics of ancestry-specific GWAS as well as multi-ancestry meta-analysis are available for download from the GWAS catalog under accession number GCP000259. Similarly, the PGS constructed in the current paper is available for download from the PGS catalog under accession number PGS0002236.

Code availability

Code used for data analysis is available at https://github.com/priestlab/aorta_houghcircle and https://github.com/cathynes/GWAS-OAD.git.

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Acknowledgements

Funding came from the Department of Veterans Affairs Office of Research and Development, MVP grant 1I01BX00264 and the NIH (R00HL130523) to J.R.P.; and a Stanford MCHRI Seed Grant to C.T. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and 11 industry partners (AbbVie, AstraZeneca, Biogen, Celgene, Celgene International II Sàrl, Genentech, Merck Sharp & Dohme, Pfizer, GlaxoSmithKline, Sanofi, Maze Therapeutics, Janssen Biotech). We acknowledge the following biobanks for collecting the FinnGen project samples: Auria Biobank (https://www.auria.fi/biopankki/), THL Biobank (https://www.thl.fi/biobank), Helsinki Biobank (https://www.helsinginbiopankki.fi/), the Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (https://www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), the Biobank of Eastern Finland (https://ita-suomenbiopankki.fi/en/), Central Finland Biobank (https://www.ksshp.fi/fi-FI/Potilaalle/Biopankki), the Finnish Red Cross Blood Service Biobank (https://www.veripalvelu.fi/verenluovutus/biopankkitoiminta) and Terveystalo Biobank (https://www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/). All Finnish biobanks are members of BBMRI.fi infrastructure (https://www.bbmri.fi). We thank D. Zanetti, M. Aguirre and M. Yu for technical assistance with aspects of the analysis and R. Kajanne for assistance with administrative aspects of the FinnGen resource.

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C.T. and J.R.P. conceived and designed the study. K.X. and H.T. performed image extraction derived from machine learning. R.J., T.B., R.L.K., S.V., M.R., D.J.R. and S.D. devised and performed the analyses of the Penn Medicine Biobank cohort under the auspices of the RGC consortium authorship. C.T., J.A.L., M.P., D.K., T.A. and P.T. devised and performed the analyses of the MVP cohort under the auspices of the VA–MVP consortium authorship. S.R., M.A.R., A.P. and M.D. devised and performed the analyses of the FinnGen cohort under the auspices of the FinnGen Project consortium authorship. C.T. performed the primary genetic analyses, and C.T. and J.R.P. performed the clinical analyses of the UK Biobank. C.T. and J.R.P. wrote the manuscript with valuable edits and input provided by all authors.

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Correspondence to James R. Priest.

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At the time of resubmission, J.R.P. is an employee of Tenaya Therapeutics, which does not have active clinical or preclinical development programs related to the data presented here. The remaining authors declare no competing interests.

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Tcheandjieu, C., Xiao, K., Tejeda, H. et al. High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease. Nat Genet 54, 772–782 (2022). https://doi.org/10.1038/s41588-022-01070-7

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