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Genetic analysis of right heart structure and function in 40,000 people

Nature Genetics volume 54, pages 792–803 (2022)Cite this article

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Abstract

Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10−13) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.

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Fig. 1: Right heart measurement with deep learning.
Fig. 2: Right heart structures are associated with PheCode-based disease definitions.
Fig. 3: Alterations in right ventricular volume with prevalent disease.
Fig. 4: Manhattan plots of right heart traits.
Fig. 5: Right heart loci.
Fig. 6: Cumulative incidence of dilated cardiomyopathy stratified by genetic prediction of RVEF.

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Data availability

UK Biobank data are made available to researchers from research institutions with genuine research inquiries, following IRB and UK Biobank approval. GWAS summary statistics are available at the Broad Institute Cardiovascular Disease Knowledge Portal (http://www.broadcvdi.org). Single nucleus RNA sequencing data are publicly available at the Single Cell Portal (https://singlecell.broadinstitute.org/single_cell accession no. SCP498). The dbGAP study accession numbers used for FHS replication were phs000007.v32.p13 for PA diameter measurement and phs000342.v20.p13 for genotyping. BBJ data are available to bona fide researchers for approved research by application to the Japanese Genotype-phenotype Archive. MGB data are available to MGB investigators. All other data are contained within the article and its Supplementary information, or are available upon reasonable request to the corresponding author.

Code availability

The code used to perform Poisson surface reconstruction from segmentation output is located at https://github.com/broadinstitute/ml4h and is available under an open-source BSD license. The code used to perform permutation testing to assess enrichment of disease-related genes near GWAS loci is located at https://github.com/carbocation/genomisc and is available under an open-source BSD license. The code used to annotate magnetic resonance images is located at https://github.com/carbocation/traceoverlay and is available under an open-source BSD license.

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Acknowledgements

We thank all participants of UK Biobank, MGB, BBJ and FHS. We acknowledge the staff of BBJ for their assistance. Cardiac magnetic resonance images in Fig. 1 are reproduced by kind permission of UK Biobank. We acknowledge Servier Medical Art (smart.servier.com) for the right heart illustration in Fig. 1, which is licensed under a Creative Commons Attribution 3.0 Unported License (CC-BY-3.0). We also acknowledge M. O’Reilly, from Pattern at the Broad Institute, for modifying the right heart illustration and for creating the remaining graphical illustrations in Fig. 1. This work was supported by grants from the National Institutes of Health K08HL159346 (J.P.P.), R01HL092577 (P.T.E.), K24HL105780 (P.T.E.), R01HL134893 (J.E.H.), R01HL140224 (J.E.H.), K24HL153669 (J.E.H.), 5T32HL007604-35 (V.N.), T32HL007208 (S. Khurshid), R01HL128914 (E.J.B.), R01HL092577 (E.J.B.), R01HL141434 (E.J.B.), U54HL120163 (E.J.B.) and R01HL139731 (S.A.L.). This work was supported by the Fondation Leducq 14CVD01 (P.T.E.). This work was supported by a John S LaDue Memorial Fellowship (J.P.P.) and the Sarnoff Cardiovascular Research Foundation Scholar Award (J.P.P.). This work was supported by the Tailor-Made Medical Treatment Program of the Ministry of Education, Culture, Sports, Science and Technology (BBJ). This work was supported by the Japan Agency for Medical Research via JP17km0305002 (BBJ), JP17km0305001 (BBJ), JP20km0405209 (BBJ, S. Koyama, K.I., I.K.) and JP20ek0109487 (BBJ, S. Koyama, K.I., I.K.). This work was supported by student scholarships from the Dutch Heart Foundation (S.J.) and the Amsterdams Universiteitsfonds (S.J.). This work was supported by grants from the NIH/NHLBI R01HL148050 (P.N.) and R01HL127564 (P.N.), NIH/NHGRI U01HG011719 (P.N.), and Massachusetts General Hospital Fireman Chair (P.N.). This work was supported by American Heart Association grants 18SFRN34110082 (E.J.B.), 18SFRN34250007 (S.A.L.) and a Strategically Focused Research Networks grant (P.T.E.). This work was supported by the Fredman Fellowship for Aortic Disease (M.E.L.) and the Toomey Fund for Aortic Dissection Research (M.E.L.). This work was funded by a collaboration between the Broad Institute and IBM Research.

Author information

Author notes

  1. These authors contributed equally: James P. Pirruccello, Paolo Di Achille, Victor Nauffal.

Authors and Affiliations

  1. Cardiology Division, Massachusetts General Hospital, Boston, MA, USA

    James P. Pirruccello, Shaan Khurshid, Pradeep Natarajan, Steven A. Lubitz, Mark E. Lindsay & Patrick T. Ellinor

  2. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    James P. Pirruccello, Shaan Khurshid, Satoshi Koyama, Pradeep Natarajan, Steven A. Lubitz, Mark E. Lindsay & Patrick T. Ellinor

  3. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    James P. Pirruccello, Paolo Di Achille, Victor Nauffal, Mahan Nekoui, Samuel F. Friedman, Marcus D. R. Klarqvist, Mark D. Chaffin, Lu-Chen Weng, Jonathan W. Cunningham, Shaan Khurshid, Carolina Roselli, Satoshi Koyama, Sean J. Jurgens, Pradeep Natarajan, Steven A. Lubitz, Mark E. Lindsay & Patrick T. Ellinor

  4. Harvard Medical School, Boston, MA, USA

    James P. Pirruccello, Mahan Nekoui, Shaan Khurshid, Pradeep Natarajan, Steven A. Lubitz, Jennifer E. Ho, Mark E. Lindsay & Patrick T. Ellinor

  5. Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Paolo Di Achille, Samuel F. Friedman, Marcus D. R. Klarqvist, Puneet Batra & Anthony A. Philippakis

  6. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Victor Nauffal & Jonathan W. Cunningham

  7. University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Carolina Roselli

  8. Framingham Heart Study, Boston University and National Heart, Lung, and Blood Institute, Framingham, MA, USA

    Honghuang Lin & Emelia J. Benjamin

  9. Division of Clinical Informatics, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Honghuang Lin

  10. Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

    Satoshi Koyama & Kaoru Ito

  11. Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Yoichiro Kamatani & Yoichiro Kamatani

  12. Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

    Yoichiro Kamatani & Yoichiro Kamatani

  13. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Issei Komuro

  14. Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Sean J. Jurgens

  15. Department of Medicine, Cardiology and Preventive Medicine Sections, Boston University School of Medicine, Boston, MA, USA

    Emelia J. Benjamin

  16. Epidemiology Department, Boston University School of Public Health, Boston, MA, USA

    Emelia J. Benjamin

  17. IBM Research, Cambridge, MA, USA

    Kenney Ng

  18. Department of Radiology, Harvard Medical School, Boston, MA, USA

    Udo Hoffmann

  19. Cardiovascular Imaging Research Center, Massachusetts General Hospital, Boston, MA, USA

    Udo Hoffmann

  20. Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA

    Steven A. Lubitz & Patrick T. Ellinor

  21. CardioVascular Institute and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Jennifer E. Ho

  22. Thoracic Aortic Center, Massachusetts General Hospital, Boston, MA, USA

    Mark E. Lindsay

  23. Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koichi Matsuda

  24. Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Koichi Matsuda

  25. Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yuji Yamanashi

  26. Division of Clinical Genome Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yoichi Furukawa

  27. Division of Molecular Pathology IMSUT Hospital, Department of Internal Medicine Project Division of Genomic Medicine and Disease Prevention The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Takayuki Morisaki

  28. Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yoshinori Murakami

  29. Department of Public Policy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Kaori Mutu & Akiko Nagai

  30. Department of Urology, Iwate Medical University, Iwate, Japan

    Wataru Obara

  31. Department of Internal Medicine and Rheumatology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Ken Yamaji

  32. Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Kazuhisa Takahashi

  33. Division of Pharmacology, Department of Biomedical Science, Nihon University School of Medicine, Tokyo, Japan

    Satoshi Asai

  34. Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan

    Satoshi Asai & Yasuo Takahashi

  35. Tokushukai Group, Tokyo, Japan

    Takao Suzuki & Nobuaki Sinozaki

  36. Department of Hematology, Nippon Medical School, Tokyo, Japan

    Hiroki Yamaguchi

  37. Department of Bioregulation, Nippon Medical School, Kawasaki, Japan

    Shiro Minami

  38. Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan

    Shigeo Murayama

  39. Fukujuji Hospital, Tokyo, Japan

    Kozo Yoshimori

  40. Japan Anti-Tuberculosis Association, Tokyo, Japan

    Kozo Yoshimori

  41. The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan

    Satoshi Nagayama

  42. Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Shiga, Japan

    Daisuke Obata

  43. Department of General Thoracic Surgery, Osaka International Cancer Institute, Osaka, Japan

    Masahiko Higashiyama

  44. Aso Iizuka Hospital, Fukuoka, Japan

    Akihide Masumoto

  45. National Hospital Organization Osaka National Hospital, Osaka, Japan

    Yukihiro Koretsune

Authors
  1. James P. Pirruccello
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  2. Paolo Di Achille
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  3. Victor Nauffal
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  4. Mahan Nekoui
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  5. Samuel F. Friedman
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  6. Marcus D. R. Klarqvist
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  7. Mark D. Chaffin
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  8. Lu-Chen Weng
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  9. Jonathan W. Cunningham
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  10. Shaan Khurshid
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  11. Carolina Roselli
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  12. Honghuang Lin
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  13. Satoshi Koyama
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  14. Kaoru Ito
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  15. Yoichiro Kamatani
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  16. Issei Komuro
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  17. Sean J. Jurgens
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  18. Emelia J. Benjamin
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  19. Puneet Batra
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  20. Pradeep Natarajan
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  21. Kenney Ng
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  22. Udo Hoffmann
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  23. Steven A. Lubitz
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  24. Jennifer E. Ho
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  25. Mark E. Lindsay
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  26. Anthony A. Philippakis
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  27. Patrick T. Ellinor
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Consortia

The BioBank Japan Project

  • Koichi Matsuda
  • , Yuji Yamanashi
  • , Yoichi Furukawa
  • , Takayuki Morisaki
  • , Yoshinori Murakami
  • , Yoichiro Kamatani
  • , Kaori Mutu
  • , Akiko Nagai
  • , Wataru Obara
  • , Ken Yamaji
  • , Kazuhisa Takahashi
  • , Satoshi Asai
  • , Yasuo Takahashi
  • , Takao Suzuki
  • , Nobuaki Sinozaki
  • , Hiroki Yamaguchi
  • , Shiro Minami
  • , Shigeo Murayama
  • , Kozo Yoshimori
  • , Satoshi Nagayama
  • , Daisuke Obata
  • , Masahiko Higashiyama
  • , Akihide Masumoto
  •  & Yukihiro Koretsune

Contributions

J.P.P. and P.T.E. conceived of the study. J.P.P. and V.N. annotated images. J.P.P. trained the deep learning models. P.D.A. performed surface reconstruction. J.P.P., V.N., M.D.C., P.D.A., S.F.F., and M.D.R.K. conducted bioinformatic analyses in UK Biobank. S. Koyama, K.I., Y. Kamatani, and I.K. performed replication analyses in BBJ. L.-C.W. performed replication analyses in MGB. H.L. performed replication analyses in FHS. J.P.P., M.E.L., and P.T.E. wrote the paper. M.N., J.W.C., S. Khurshid, C.R., S.J.J., E.J.B., P.B., P.N., K.N., U.H., S.A.L., J.E.H., and A.A.P. contributed to the analysis plan or provided critical revisions.

Corresponding author

Correspondence to Patrick T. Ellinor.

Ethics declarations

Competing interests

J.P.P. has served as a consultant for Maze Therapeutics. P.B. is supported by grants from Bayer AG and IBM applying machine learning in cardiovascular disease. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim and Fitbit, has consulted for Bristol Myers Squibb/Pfizer and Bayer AG and participates in a research collaboration with IBM. K.N. is employed by IBM Research. 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. 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. P.T.E. received sponsored research support from Bayer AG and IBM Research. P.T.E. has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. P.N. reports investigator-initated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a shareholder of geneXwell and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. 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. All remaining authors report no competing interests.

Peer review

Peer review information

Nature Genetics thanks Heribert Schunkert, Eric Villard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

Supplementary Information

Supplementary Note and Figs. 1–22.

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Supplementary Tables

Supplementary Tables 1–22.

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Pirruccello, J.P., Di Achille, P., Nauffal, V. et al. Genetic analysis of right heart structure and function in 40,000 people. Nat Genet 54, 792–803 (2022). https://doi.org/10.1038/s41588-022-01090-3

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  • DOI: https://doi.org/10.1038/s41588-022-01090-3

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