Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy

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Abstract

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.

Abstract

Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.

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Opportunities and challenges for transcriptome-wide association studies

Michael Wainberg, Nasa Sinnott-Armstrong, Nicholas Mancuso … (2019)

Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn’s disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene as well as loci where TWAS prioritizes multiple genes, some likely to be non-causal, owing to sharing of expression quantitative trait loci (eQTL). TWAS is especially prone to spurious prioritization with expression data from non-trait-related tissues or cell types, owing to substantial cross-cell-type variation in expression levels and eQTL strengths. Nonetheless, TWAS prioritizes candidate causal genes more accurately than simple baselines. We suggest best practices for causal-gene prioritization with TWAS and discuss future opportunities for improvement. Our results showcase the strengths and limitations of using eQTL datasets to determine causal genes at GWAS loci.

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Reference ranges for cardiac structure and function using cardiovascular magnetic resonance (CMR) in Caucasians from the UK Biobank population cohort

Steffen Petersen, Nay Aung, Mihir M Sanghvi … (2017)

Background Cardiovascular magnetic resonance (CMR) is the gold standard method for the assessment of cardiac structure and function. Reference ranges permit differentiation between normal and pathological states. To date, this study is the largest to provide CMR specific reference ranges for left ventricular, right ventricular, left atrial and right atrial structure and function derived from truly healthy Caucasian adults aged 45–74. Methods Five thousand sixty-five UK Biobank participants underwent CMR using steady-state free precession imaging at 1.5 Tesla. Manual analysis was performed for all four cardiac chambers. Participants with non-Caucasian ethnicity, known cardiovascular disease and other conditions known to affect cardiac chamber size and function were excluded. Remaining participants formed the healthy reference cohort; reference ranges were calculated and were stratified by gender and age (45–54, 55–64, 65–74). Results After applying exclusion criteria, 804 (16.2%) participants were available for analysis. Left ventricular (LV) volumes were larger in males compared to females for absolute and indexed values. With advancing age, LV volumes were mostly smaller in both sexes. LV ejection fraction was significantly greater in females compared to males (mean ± standard deviation [SD] of 61 ± 5% vs 58 ± 5%) and remained static with age for both genders. In older age groups, LV mass was lower in men, but remained virtually unchanged in women. LV mass was significantly higher in males compared to females (mean ± SD of 53 ± 9 g/m2 vs 42 ± 7 g/m2). Right ventricular (RV) volumes were significantly larger in males compared to females for absolute and indexed values and were smaller with advancing age. RV ejection fraction was higher with increasing age in females only. Left atrial (LA) maximal volume and stroke volume were significantly larger in males compared to females for absolute values but not for indexed values. LA ejection fraction was similar for both sexes. Right atrial (RA) maximal volume was significantly larger in males for both absolute and indexed values, while RA ejection fraction was significantly higher in females. Conclusions We describe age- and sex-specific reference ranges for the left ventricle, right ventricle and atria in the largest validated normal Caucasian population. Electronic supplementary material The online version of this article (doi:10.1186/s12968-017-0327-9) contains supplementary material, which is available to authorized users.

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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

Alexander Gusev, Nicholas Mancuso, Hyejung Won … (2018)

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS significant genes, of which 35 did not overlap a known GWAS locus. 42/157 genes were associated to specific chromatin features measured in independent samples, highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, MAPK3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from brain captured the majority of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving towards a mechanistic understanding of GWAS.

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Author and article information

Contributors

Krishna G. Aragam: karagam@mgh.harvard.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 7 May 2020

Publication date PMC-release: 7 May 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 2254

Affiliations

[1 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Division of Cardiology, Massachusetts General Hospital, ; Boston, MA USA

[2 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Genomic Medicine, Massachusetts General Hospital, ; Boston, MA USA

[3 ]GRID grid.66859.34, Program in Medical and Population Genetics, Broad Institute, ; Cambridge, MA USA

[4 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Medicine, Massachusetts General Hospital, ; Boston, MA USA

[5 ]GRID grid.66859.34, Data Sciences Platform, Broad Institute, ; Cambridge, MA USA

[6 ]ISNI 0000 0004 0521 0744, GRID grid.279946.7, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, ; Torrance, CA USA

[7 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Radiology, Johns Hopkins University, ; Baltimore, MA USA

[8 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, ; Baltimore, MA USA

[9 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, ; Baltimore, MA USA

[10 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Center for Public Health Genomics, University of Virginia, ; Charlottesville, VA USA

[11 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Division of Cardiology, Johns Hopkins University School of Medicine, ; Baltimore, MA USA

[12 ]GV, Mountain View, CA USA

[13 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; Boston, MA USA

[14 ]Verve Therapeutics, Cambridge, MA USA

Author information

James P. Pirruccello http://orcid.org/0000-0001-6088-4037

Minxian Wang http://orcid.org/0000-0002-3753-508X

Mark Chaffin http://orcid.org/0000-0002-1234-5562

Stephen Rich http://orcid.org/0000-0003-3872-7793

Joao A. C. Lima http://orcid.org/0000-0001-8756-6995

Sekar Kathiresan http://orcid.org/0000-0002-6724-032X

Article

Publisher ID: 15823

DOI: 10.1038/s41467-020-15823-7

PMC ID: 7206184

PubMed ID: 32382064

SO-VID: 8bf778e3-b678-4f90-866a-28b1ab241e83

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 July 2019

Date accepted : 18 March 2020

Funding

Funded by: John S LaDue Memorial Fellowship for Cardiovascular Research

Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);

Award ID: 1R01HL139731

Award ID: R01HL128914

Award ID: K24HL105780

Award ID: HL127564

Award Recipient : Steven A. Lubitz Patrick T. Ellinor Sekar Kathiresan

Funded by: FundRef https://doi.org/10.13039/100000968, American Heart Association (American Heart Association, Inc.);

Award ID: 18SFRN34250007

Award ID: 18SFRN34110082

Award ID: 17IFUNP33840012

Award Recipient : Steven A. Lubitz Patrick T. Ellinor Krishna G. Aragam

Funded by: FundRef https://doi.org/10.13039/501100001674, Fondation Leducq;

Award ID: 14CVD01

Award Recipient : Patrick T. Ellinor

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ScienceOpen disciplines: Uncategorized

Keywords: genome-wide association studies,cardiovascular genetics,cardiomyopathies

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ScienceOpen disciplines: Uncategorized

Keywords: genome-wide association studies, cardiovascular genetics, cardiomyopathies

Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy

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Electron Channelling Contrast Imaging (ECCI)

Most cited references 30

Opportunities and challenges for transcriptome-wide association studies

Reference ranges for cardiac structure and function using cardiovascular magnetic resonance (CMR) in Caucasians from the UK Biobank population cohort

Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

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