Olesen Group - Cardiac Genetics

The Olesen Group is highly involved in research in the field of genetic causes of cardiac arrhythmia.

Research focus

Olesen Group has a long track record in genetic studies of arrhythmia disorders. Olesen Group is one of the leading groups in a large consortium that has performed the largest genome wide association study (GWAS) on atrial fibrillation (AF). Using this approach, they contributed to the identification of more than 100 loci that were significantly associated with an increased risk of developing AF (Roselli et al. In Nature Genetic)

Olesen Group has also conducted a study of rare coding variants in AF patients (so called whole exome sequencing). This study demonstrated how the combination of human genetics and the zebrafish model can add invaluable knowledge to our understanding of disease mechanisms.

The study demonstrated that rare truncating mutations (TTNtv) in the large sarcomere gene were associated with an odds ratio (OR) of 30 for AF.

Functional studies in zebrafish atria showed that TTNtv leads to conduction-delay, atrial, sarcomere defect, increased fibrosis and cardiomyopathy (Ahlberg et al. in Nature Comm 2018).

Resent evidence suggests that atrial cardiomyopathy is an independent predictor of stroke risk. Olesen Group have therefore conducted a GWAS study of of 50.000 cMRI from Biobank to study atrial structure and function. This GWAS identified 18 genes associated with atrial cardiomyopathies (Ahlberg et al. in EHJ 2021).

Techniques

Next Generation Sequencing and GWAS

For many years, the gold standard method of gene sequencing has been the Sanger sequencing method where one had to select candidate genes that were subsequently analyzed one by one.

Within the last years, technology in genetic sequencing has evolved greatly, resulting in a plethora of new techniques, collectively named Next Generation Sequencing. With next generation sequencing, the entire DNA (genome) or major parts of it (e.g. all protein coding regions = the exome) can be analyzed in just one analysis and requiring only a few days to obtain the results.

We are also conduction GWAS to understand genetic complex cardiovascular diseases such as atrial fibrillation (AF), atrial cardiomyopathy and syncope.

Research projects

We are currently investigating the genetics of atrial fibrillation (Ahlberg et al. in Nature Comm, 2018), atrial cardiomyopathic (Ahlberg et al. in EHJ, 2022), venous thromboembolism (Ghouse et al. in Nature Genetics, 2023), adverse drug effects of ACE inhibitors (Ghouse et al. in EHJ , 2022 and Ghouse et al. in JACC, 2021).

Main findings

Genetics has made it possible to understand the most important diseases pathway. It is also possible to make polygenetic risk scores to identify which patients are in high risk of developing a given cardiovascular disease.

International collaborations

Some of our zebrafish projects are done in collaboration with Prof. Didier Stainier, from the Max Planck Institute for Heart and Lung research, Bad Nauheim, Germany. Prof. Stainier is a world-leading researcher in heart development in zebrafish (Collins et al., PNAS, 2019, IF 9.5). We furthermore have a collaboration with Prof. Torben Hansen (The Novo Nordisk Centre for Basic Metabolic Research) which has resulted in two papers with me as the last author (Ghouse et al. in European Heart Journal, 2015, IF 30 and Ghouse et al, GIM, 2016, IF 10).

In addition, for the preceding five years, I have been part of the AFGEN consortium, headed by Prof. Patrick Ellinor, The Broad Institute/Harvard University, USA. (Sinner et al. in Circulation, 2012, Roselli et al. in Nature Gen 2018, Ntalla et al. in Nature Comm, 2020). Finally, we have a collaboration with Prof. Bezzina, Dep of Exp. Cardiology, Amsterdam (Bezzina et al. in Nature Gen, 2013, Lahrouchi et al. in Circulation, 2020 and Walsh et al. in GIM, 2020).

Publications