L'unité de recherche de l'institut du thorax
Inserm UMR 1087 / CNRS UMR 6291 IRS - Université de Nantes 8 quai Moncousu BP 70721
44007 Nantes 1
L’institut du thorax (ITX) is a structure at the forefront of translational research against sudden
cardiac death (SCD). Our primary objective is to improve healthcare by combining basic research
and clinical activity into translational research programs. Within the ITX, the ‘Cardiovascular
Genetics’ team develops state-of-the-art projects to elucidate the genetic basis of cardiac
The Brugada syndrome (BrS) is one such disorder characterized by ST-segment elevation in the
right precordial ECG leads and associated with increased risk of SCD. The BrS has been firstly
described as a Mendelian disorder with the identification of rare variants (mainly found within the
SCN5A gene encoding the major cardiac sodium channel Na V 1.5) either in isolated or within
familial cases. In 2013, we reported a genome-wide association study (GWAS) that identified 3
common haplotypes increasing the risk to develop the disease (Bezzina et al Nat Genetics 2013).
We have now extended this GWAS by including over 2,800 BrS cases recruited within a large
international consortium and have identified 21 variants (all located in non-coding regions) that
increase dramatically the risk of BrS and thus are likely relevant to the broader problem of SCD.
In parallel, we have recently constructed a reference panel of whole-genome sequences from
800 healthy individuals of French ancestry. Based on this resource, we have initiated a WGS-
based association study on BrS by sequencing the whole genomes of 350 unrelated patients of
French origin. Our project is part of an international effort on BrS, which will also include 500
cases of Dutch and British origins, enabling us to investigate the full spectrum of risk variants
(rare, common and intermediate frequency variants; point mutation, small insertion deletion and
copy number variations) potentially involved in BrS. This approach opens unique opportunities to
interrogate the full spectrum genetic variations so far unexplored such as the low-frequency
(MAF<5%) and variants in the non-coding region of the genome, seat of the gene regulation.
The PhD project is to carry out the WGS-based association study on the French but also the
Dutch and UK samples. Interrogating the different types of variations (point mutation, small
insertion deletion and copy number variations) will require applying and/or adapting calling
methods prior to association testing. Furthermore aside from the type of variants, the location of
the variants (coding or non-coding region) will constitute a sub-type of analysis and will require
performing functional annotations. This last part will be performed in parallel to a complementary
ongoing program dedicated to cardiac epigenetics program.