NCT04183023 - Population Genomic Diversity of France

The development of high throughput sequencing technologies has opened-up new possibilities to sequence the human genome and identify all genetic variants in individual genome. In each genome, more than four million differences from the reference sequence, i.e. variants, are found and the real challenge is to find "the needles in stacks of needles". A majority of these variants are neutral with no impact on individual phenotype but some of them could impair individual health and lead to disease. Guidelines have been proposed for implicating sequence variants in diseases and limiting false positive reports. In these guidelines, emphasis is put on the requirement to compare the distributions of variants between patients and large control datasets matched as closely as possible to the patients in terms of ancestry. Several large reference datasets such as those from the 1000 Genomes Project Consortium, the Exome Sequencing Project (ESP) or the Exome Aggregation Consortium (ExAC) are publicly available and give information on the variants found in the exomes or whole genomes of individuals with ancestries in different populations and their respective frequencies. Europeans are well represented in this database. However, there is no information on the geographic region in Europe where individuals are originating from, except for the Finns that are considered separately from the rest of Europe. Previous studies using SNP-chips have shown however that there exist some differences in allele frequencies between continental European populations and that these differences could lead to false positive results in association studies. These allele frequency differences at common variants are also detectable between regions within a country as found by several studies on different European populations, including France. It is very important to describe these geographic fine-scale stratification patterns to allow an efficient matching of cases and controls in association studies. This is especially true when the interest is on rare variants as these variants are, for the majority, young variants that have recently appeared in local populations and not spread over large geographic regions. Having access to DNA sequences from individuals that share common ancestry with patients is also of interest when analysing individual genomes for diagnoses. Information regarding allele frequency distribution in the same geographic areas where patients have ancestry will therefore be necessary to help select the variants that are the most likely involved in disease and should hence be tested in functional assays. A first project focusing on the western part of France is ongoing at Institut du Thorax in Nantes. Preliminary results have shown that using this panel of individuals improve variant filtering in the genomes of patients with similar ancestries. Efforts should therefore be made to cover other geographic regions of France. To provide such a general population panel for France, the POPGEN project will select 10,000 individuals from CONSTANCES cohort with ancestry in different regions of France outside western part. These participants will have their DNA extracted from salivary kits and genotyped using SNP-chip. Among these 10,000 individuals, 4,000 individuals will have their whole genome sequenced. This study is one of the four pilot projects of the France Genomic Medicine plan (FMG 2025). The FMG2025 plan aims at introducing genome sequencing in the routine clinical practice to accelerate and improve diagnoses. The POPGEN project will provide the required references from the general French population to help filter out common variants from the genomes of patients.