Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - MOvE-ECG (Moving from genome wide association to elucidating causal mechanisms of electrocardiographic traits)
Teaser
Understanding how genes and genetic variants influence heart function is of major importance, not only from a basic science viewpoint, but also as a foundation for future innovation in medicine and health-care. In this proposal, Dr. Niek Verweij aims to identify novel genes...
Summary
Understanding how genes and genetic variants influence heart function is of major importance, not only from a basic science viewpoint, but also as a foundation for future innovation in medicine and health-care. In this proposal, Dr. Niek Verweij aims to identify novel genes and mechanisms underlying heart growth. This will be done in collaboration with the top-scientist Dr. Chris Newton-Cheh (Harvard/Massachusetts General Hospital, Broad Institute of Harvard and MIT) and Dr. Laurie Boyer (MIT). As heart growth accompanies many forms of heart disease, this project will focus on the QRS-complex (of the electrocardiogram) in population based studies as this reflects electrically active cardiac mass.
1) We will search for novel low-frequency genetic variants associated with the QRS-complex within the CHARGE consortium and within a Dutch population using dedicated reference panels.
2) Loci will be interrogated through the use of published and unpublished in silico big-data sets to further prioritize variants and regions for experimental follow-up aimed at elucidating biological mechanisms.
This project will bridge the gap between population based genetic association studies and functional biology. This proposal will provide novel insights into cardiomyocyte functioning and provide novel avenues to study heart disease vulnerability and design innovative treatment.
Work performed
Increased electrocardiographic left ventricular mass (eLVM) is a characteristic of and risk factor for heart failure, as well as mortality in the general population. Prior genetic studies of eLVM focused primarily on common variants, most of which are non-coding. The role of low-frequency (MAF 0.01-0.05) and rare (MAF <0.01) coding variants underlying eLVM remain unexplored. In order to better understand the genetic determinants of eLVM, we tested the association between 246,516 variants on the Infinium HumanExome BeadChip, mostly coding and low-frequency/rare, with 3 EKG measures of eLVM: products of QRS duration and a) 12-lead sum (12LS), b) Sokolow-Lyon (S-L), and c) Cornell (C) voltage. 73,647 individuals of European (n=63,859), African American (n=7,741), Hispanic (n=1,322) and East Asian (n=725) ancestries were genotyped in 19 participating cohorts (AGES, ARIC, BRIGHT, CHS, CROATIA, GS, GRAPHIC, INTER99, JHS, KORA, LIFELINES, MESA, NEO, RSI, SHIP, WHI and YFS) of the CHARGE EKG consortium. Single variant association tests in each cohort were performed using RAREMETALWORKER, and results were combined using fixed effects meta-analysis in RAREMETAL, using P<1x10-8 as a genome-wide significant threshold. We identified variants at 31 independent loci (18 coding, 6 intronic and 7 intergenic) significant for at least one eLVM phenotype, representing 21 novel and 10 previously reported associations. We then evaluated the effects of rare/low-frequency coding variants in aggregate in gene-based tests using SKAT, identifying 7 genes at exome-wide significance (P<1x10-6): TTN (P=3.1x10-15), DSP (P=1.3x10-14), KLHL38 (P=1.8x10-10), FLII (P=3.1x10-10), RPL3L (P=7.9x10-8), CD36 (P=1.8x10-7) and DLEC1 (P=2.2x10-7). Associations at genes except for TTN were each explained by a single missense low-frequency variant. The TTN SKAT association lost significance (P=0.99) after adjusting for the two most significant low-frequency variants, although a common variant remained significant (P=5.4x10-11). TTN encodes titin, a protein that influences passive elasticity of cardiomyocytes, and DSP encodes desmoplakin, an essential component of intercellular junctions in cardiomyocytes; both are known to harbor rare coding mutations as causes of Mendelian cardiomyopathy. Taken together, we have identified 21 novel loci harboring common variants and 7 genes harboring rare/low-frequency coding variants associated with eLVM, of which several demonstrate tissue-specific expression in the heart. We are currently performing fine-mapping of loci and screening potential functional variants.
Final results
Heart failure (HF) is an important contributor to both the burden and cost of healthcare expenditures, with older people suffering from HF more than from any other medical condition. With the aging of the population, the impact of HF is expected to increase substantially. Despite few advances in pharmacological treatment of HF, the prognosis remains very poor. The results of this project will advance our knowledge surrounding cardiomyocyte dysfunction which will eventually lead to novel therapeutic targets, better risk assessment and progress HF-health care and contribute to healthy ageing. In contrast to relative stagnation of HF-treatment, remarkable progress has been made in understanding human genetics, enabled by the sequence of the human genome and technologies for DNA analysis. To date, understanding the functional consequences of genetic variation is eagerly awaited in biomedical and genetic research. This study may provide detailed insight into cardiomyocyte functioning, HF vulnerability and provide a pipeline approach to other groups performing similar studies, though in different organ systems.