Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers

The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, other carriers remain asymptomatic or show only mild symptoms in old age. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N=48) showed shorter QRS duration (-5.73 ms, p-value=0.001) compared to asymptomatic non-carriers and symptomatic carriers (N=26), and we replicated this in different subset of 21,771 participants from the Lifelines cohort (-3.87 ms, p-value=0.028) and in 592 carriers from the Arrhythmogenic Cardiomyopathy (ACM) patient registry (-6.91 ms, p-value=0.0002). Furthermore, symptomatic carriers showed a higher correlation between genetic predisposition to higher QRS duration (PGSQRS) and QRS (p-value=1.98x10-8), suggesting that symptomatic PLN c.40_42delAGA carriers may have an increased sensitivity to the effect of genetic variation in cardiac rhythm. Our results may help improve risk prediction models for cardiac outcomes for future studies, while our approach could guide studies on genetic diseases with incomplete penetrance.

[1]  C. Bezzina,et al.  When genetic burden reaches threshold , 2020, European heart journal.

[2]  Shing Wan Choi,et al.  The power of pathway-based polygenic risk scores , 2021 .

[3]  W. Shimizu,et al.  Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers , 2017, Circulation. Cardiovascular genetics.

[4]  T. Spector,et al.  Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies , 2009, PloS one.

[5]  Terry M. Therneau,et al.  Mixed Effects Cox Models , 2015 .

[6]  Gaël Varoquaux,et al.  Scikit-learn: Machine Learning in Python , 2011, J. Mach. Learn. Res..

[7]  M. Farrall,et al.  Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity , 2021, Nature Genetics.

[8]  A. Zhernakova,et al.  Lack of Association Between Genetic Variants at ACE2 and TMPRSS2 Genes Involved in SARS-CoV-2 Infection and Human Quantitative Phenotypes , 2020, Frontiers in Genetics.

[9]  A. Teumer,et al.  The genetic makeup of the electrocardiogram , 2019, bioRxiv.

[10]  Xavier Robin,et al.  pROC: an open-source package for R and S+ to analyze and compare ROC curves , 2011, BMC Bioinformatics.

[11]  M. Rieder,et al.  Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. , 2012, American journal of human genetics.

[12]  M. Kanai,et al.  Global biobank analyses provide lessons for computing polygenic risk scores across diverse cohorts , 2021, medRxiv.

[13]  J. Hirschhorn,et al.  DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease , 2008, Proceedings of the National Academy of Sciences.

[14]  D. Judge,et al.  Epidemiology of the inherited cardiomyopathies , 2020, Nature Reviews Cardiology.

[15]  G. MacGowan,et al.  Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy , 2020, BMC Cardiovascular Disorders.

[16]  A. Zwinderman,et al.  Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers–reaching the frontiers of individual risk prediction , 2021, European heart journal.

[17]  E. Dermitzakis,et al.  Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33 , 2010, Nature Genetics.

[18]  T. Akgun,et al.  Variations of QRS Morphology in Patients with Dilated Cardiomyopathy; Clinical and Prognostic Implications , 2014, Journal of cardiovascular and thoracic research.

[19]  P. Elliott,et al.  Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect , 2020, Nature Genetics.

[20]  Hae Kyung Im,et al.  Survey of the Heritability and Sparse Architecture of Gene Expression Traits across Human Tissues , 2016, bioRxiv.

[21]  Josyf Mychaleckyj,et al.  Robust relationship inference in genome-wide association studies , 2010, Bioinform..

[22]  R. Hauer,et al.  Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy , 2012, European journal of heart failure.

[23]  G. Dorn,et al.  A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[24]  H. Bundgaard,et al.  Genotype–phenotype correlation in arrhythmogenic right ventricular cardiomyopathy—risk of arrhythmias and heart failure , 2021, Journal of Medical Genetics.

[25]  P. Munroe,et al.  Genetically Determined Serum Calcium Levels and Markers of Ventricular Repolarization , 2021, Circulation. Genomic and precision medicine.

[26]  Gonçalo R. Abecasis,et al.  Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia , 2008, Proceedings of the National Academy of Sciences.

[27]  Seunggeun Lee,et al.  UK-Biobank Whole Exome Sequence Binary Phenome Analysis with Robust Region-based Rare Variant Test , 2019, bioRxiv.

[28]  Xihong Lin,et al.  Rare-variant association testing for sequencing data with the sequence kernel association test. , 2011, American journal of human genetics.

[29]  D. Panagiotakos,et al.  Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy. , 2016, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[30]  A. Lai,et al.  Could personalised risk prediction for type 2 diabetes using polygenic risk scores direct prevention, enhance diagnostics, or improve treatment? , 2020 .

[31]  Skipper Seabold,et al.  Statsmodels: Econometric and Statistical Modeling with Python , 2010, SciPy.

[32]  B. de Jonge,et al.  Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy , 2020, bioRxiv.

[33]  Jingyuan Fu,et al.  Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction , 2010, Nature Genetics.

[34]  Eloisa Arbustini,et al.  Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. , 2007, European heart journal.

[35]  P. Thompson,et al.  The athlete's heart. , 1997, Clinics in sports medicine.

[36]  Ross M. Fraser,et al.  A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness , 2014, PLoS genetics.

[37]  Mary Goldman,et al.  Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics , 2016, Nature Communications.

[38]  A. V. van Roon,et al.  Determinants of heart rate variability in the general population: The Lifelines Cohort Study. , 2018, Heart rhythm.

[39]  C. Wijmenga,et al.  Cohort Profile Cohort Profile : LifeLines , a three-generation cohort study and biobank , 2015 .

[40]  E. Kranias,et al.  Calcium: Phospholamban: a crucial regulator of cardiac contractility , 2003, Nature Reviews Molecular Cell Biology.

[41]  Yang Ni,et al.  Polygenic prediction via Bayesian regression and continuous shrinkage priors , 2018, Nature Communications.

[42]  Paolo Ajmone-Marsan,et al.  GHap: an R package for genome-wide haplotyping , 2016, Bioinform..

[43]  Jamie I. Vandenberg,et al.  Heritability of ECG Biomarkers in the Netherlands Twin Registry Measured from Holter ECGs , 2016, Front. Physiol..

[44]  Joao A. C. Lima,et al.  Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy , 2020, Nature Communications.

[45]  Xihong Lin,et al.  Operating characteristics of the rank‐based inverse normal transformation for quantitative trait analysis in genome‐wide association studies , 2019, Biometrics.

[46]  Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits , 2019, European Journal of Human Genetics.

[47]  R. Hauer,et al.  The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update , 2019, Netherlands Heart Journal.

[48]  Christian Gieger,et al.  Genome-wide association analysis identifies multiple loci related to resting heart rate. , 2010, Human molecular genetics.

[49]  Kathleen F. Kerr,et al.  PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity , 2018, Nature Communications.

[50]  Christopher. Simons,et al.  Machine learning with Python , 2017 .

[51]  Michael A. Burke,et al.  Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies , 2016, Scientific Reports.

[52]  J. Mogensen,et al.  Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives , 2020, Circulation. Heart failure.

[53]  Kaanan P. Shah,et al.  A gene-based association method for mapping traits using reference transcriptome data , 2015, Nature Genetics.

[54]  D. Ledbetter,et al.  Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders , 2019, Nature Communications.

[55]  J. G. Post,et al.  Recurrent and founder mutations in the Netherlands—Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy , 2013, Netherlands Heart Journal.

[56]  K. Swedberg,et al.  Clinical implications of QRS duration in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction. , 2008, JAMA.