TY - JOUR
T1 - Genome-wide analysis of left ventricular image-derived phenotypes identifies fourteen loci associated with cardiac morphogenesis and heart failure development
AU - Aung, Nay
AU - Vargas, Jose D.
AU - Yang, Chaojie
AU - Cabrera, Claudia P.
AU - Warren, Helen R.
AU - Fung, Kenneth
AU - Tzanis, Evan
AU - Barnes, Michael R.
AU - Rotter, Jerome I.
AU - Taylor, Kent D.
AU - Manichaikul, Ani W.
AU - Lima, Joao A.C.
AU - Bluemke, David A.
AU - Piechnik, Stefan K.
AU - Neubauer, Stefan
AU - Munroe, Patricia B.
AU - Petersen, Steffen E.
N1 - Funding Information:
Dr Aung is supported by a Wellcome Trust Research Training Fellowship (203553/Z/16/Z). Drs Petersen, Neubauer, and Piechnik acknowledge the British Heart Foundation for funding the manual analysis to create a cardiovascular magnetic resonance imaging reference standard for the UK Biobank imaging resource in 5000 CMR scans (PG/14/89/31194). This work was part of the portfolio of translational research of the National Institute for Health Research Biomedical Research Centre at Barts and The London School of Medicine and Dentistry; Drs Cabrera, Barnes, Warren, Munroe, and Petersen acknowledge support from this center. Dr Petersen also acknowledges support from the “SmartHeart” Engineering and Physical Sciences Research Council program grant (EP/P001009/1). Drs Piechnik and Neubauer are supported by the Oxford National Institute for Health Research Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. This project was enabled through access to the Medical Research Council eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant No. MR/L016311/1). Dr Fung is supported by The Medical College of Saint Bartholomew’s Hospital Trust, an independent registered charity that promotes and advances medical and dental education and research at Barts and The London School of Medicine and Dentistry. The UK Biobank was established by the Wellcome Trust medical charity, the Medical Research Council, the Department of Health, the Scottish Government, and the Northwest Regional Development Agency. It has also received funding from the Welsh Assembly Government and the British Heart Foundation. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by National Heart, Lung, and Blood Institute contract N02-HL-64278. Genotyp-ing was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and the Massachusetts Institute of Technology (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/10/15
Y1 - 2019/10/15
N2 - BACKGROUND: The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present. METHODS: The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events. RESULTS: The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genomewide significant loci (3 loci each for LV end-diastolic volume, LV endsystolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent P<1×10-8. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (P<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (TTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB, and MMP11) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score). CONCLUSIONS: We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.
AB - BACKGROUND: The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present. METHODS: The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events. RESULTS: The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genomewide significant loci (3 loci each for LV end-diastolic volume, LV endsystolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent P<1×10-8. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (P<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (TTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB, and MMP11) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score). CONCLUSIONS: We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.
KW - Genome-wide association study
KW - Heart failure
KW - Left ventricle
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U2 - 10.1161/CIRCULATIONAHA.119.041161
DO - 10.1161/CIRCULATIONAHA.119.041161
M3 - Article
C2 - 31554410
AN - SCOPUS:85073184260
VL - 140
SP - 1318
EP - 1330
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 16
ER -