@article{52077d2405f4489e8c9d25747cd34c0d,
title = "Deep learning enables genetic analysis of the human thoracic aorta",
abstract = "Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32–1.54, P = 3.3 × 10−20). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images.",
author = "Pirruccello, {James P.} and Chaffin, {Mark D.} and Chou, {Elizabeth L.} and Fleming, {Stephen J.} and Honghuang Lin and Mahan Nekoui and Shaan Khurshid and Friedman, {Samuel F.} and Bick, {Alexander G.} and Alessandro Arduini and Weng, {Lu Chen} and Choi, {Seung Hoan} and Akkad, {Amer Denis} and Puneet Batra and Tucker, {Nathan R.} and Hall, {Amelia W.} and Carolina Roselli and Benjamin, {Emelia J.} and Vellarikkal, {Shamsudheen K.} and Gupta, {Rajat M.} and Stegmann, {Christian M.} and Dejan Juric and Stone, {James R.} and Vasan, {Ramachandran S.} and Ho, {Jennifer E.} and Udo Hoffmann and Lubitz, {Steven A.} and Philippakis, {Anthony A.} and Lindsay, {Mark E.} and Ellinor, {Patrick T.}",
note = "Funding Information: J.P.P. and A.G.B. have served as consultants for Maze Therapeutics. A.-D.A. and C.M.S. are employees of Bayer US LLC (a subsidiary of Bayer AG), and may own stock in Bayer AG. D.J. is supported by grants from Genentech, Eisai, EMD Serono, Takeda, Amgen, Celgene, Placon Therapeutics, Syros, Petra Pharma, InventisBio, Infinity Pharmaceuticals and Novartis. D.J. has also received personal fees from Genentech, Eisai, EMD Serono, Ipsen, Syros, Relay Therapeutics, MapKure, Vibliome, Petra Pharma and Novartis. A.A.P. is employed as a Venture Partner at GV; he is also supported by a grant from Bayer AG to the Broad Institute focused on machine learning for clinical trial design. J.E.H. is supported by a grant from Bayer AG focused on machine learning and cardiovascular disease and a research grant from Gilead Sciences. J.E.H. has received research supplies from EcoNugenics. P.B. is supported by grants from Bayer AG and IBM applying machine learning in cardiovascular disease. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P.T.E. has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim and Fitbit, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG, and participates in a research collaboration with IBM. The Broad Institute has filed for a patent on an invention from P.T.E., M.E.L. and J.P.P. related to a genetic risk predictor for aortic disease. Funding Information: This work was supported by the Fondation Leducq grant no. 14CVD01 (P.T.E.); by grants from the National Institutes of Health no.1R01HL092577 (P.T.E.), no. R01HL128914 (P.T.E.), no. K24HL105780 (P.T.E.), no. R01HL134893 (J.E.H.), no. R01HL140224 (J.E.H.), no. 5K01HL140187 (N.R.T.), no. T32HL007208 (S.K.), no. R01HL128914 (E.J.B.), no. 2R01HL092577 (E.J.B.), no. 1R01HL141434 (E.J.B.), no. 2U54HL120163 (E.J.B.), no. 1R01HL139731 (S.A.L.), no. T32HL007208 (E.L.C.), no. K08HL159346 (J.P.P.); by a grant from the American Heart Association Strategically Focused Research Networks (P.T.E.); by the American Heart Association grants no. 18SFRN34110082 (E.J.B.), no. 18SFRN34110082 (A.W.H.), no. 18SFRN34110082 (L.-C.W.), no. 18SFRN34250007 (S.A.L.); by a John S LaDue Memorial Fellowship (J.P.P.); by a Sarnoff Scholar Award (J.P.P.); by a Career Award for Medical Scientists from the Burroughs Wellcome Fund (A.G.B.); and by the Fredman Fellowship for Aortic Disease (M.E.L.) and the Toomey Fund for Aortic Dissection Research (M.E.L.). The Precision Cardiology Laboratory is a joint effort between the Broad Institute and Bayer AG. The rapid autopsy effort was funded by the Susan Eid Tumor Heterogeneity Initiative. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jan,
doi = "10.1038/s41588-021-00962-4",
language = "English (US)",
volume = "54",
pages = "40--51",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "1",
}