Genome-wide studies of heart failure and endophenotypes: lessons learned and future directions

Maaike Yldau van der Ende, Mir Abdullah Said, Dirk Jan van Veldhuisen, Niek Verweij, Pim van der Harst

Research output: Contribution to journalReview articlepeer-review


Heart failure (HF) is a complex clinical syndrome resulting from structural or functional impairments of ventricular filling or ejection of blood. HF has a poor prognosis and the burden to society remains tremendous. The unfulfilled expectation is that expanding our knowledge of the genetic architecture of HF will help to quickly advance the quality of risk assessment, diagnoses, and treatment. To date, genome-wide association studies (GWAS) of HF have led to disappointing results with only limited progress in our understanding and tempering the earlier expectations. However, the analyses of traits closely related to HF (also called 'endophenotypes') have led to promising and novel findings. For example, GWAS of NT-proBNP levels not only identified variants in the NNPA-NPPB locus but also substantiated data suggesting that natriuretic peptides in itself are associated with a lower risk of hypertension and HF. Many other genetic associates currently await experimental follow-up in which genes are prioritized based on bioinformatic analyses and various model organisms are employed to obtain functional insights. Promising genes with identified function could later be used in personalized medicine. Also, targeting specific pathogenic gene mutations is promising to protect future generations from HF, such as recently done in human embryos carrying the cardiomyopathy-associated MYBPC3 mutation. This review discusses the current status of GWAS of HF and its endophenotypes. In addition, future directions such as functional follow-up and application of GWAS results are discussed.

Original languageEnglish
Pages (from-to)1209-1225
Number of pages17
JournalCardiovascular research
Issue number9
Publication statusPublished - 15 Jul 2018
Externally publishedYes


  • Diffusion of Innovation
  • Forecasting
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study/history
  • Heart Failure/diagnosis
  • History, 20th Century
  • History, 21st Century
  • Humans
  • Phenotype
  • Prognosis
  • Risk Factors


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