POPGEN: building a reference panel of local ancestry to study genetic variability across metropolitan France

Understanding the fine-scale genetic structure of human populations is essential for both demographical history and genomic medicine. The POPGEN project was initiated as part of the France Genomic Medicine Initiative to construct a whole-genome reference panel representative of the ancestral genetic diversity that existed across metropolitan France at the beginning of the 20th century. Building on previous studies that reported significant fine-scale population structure within France, POPGEN aimed to improve geographic coverage and generate regional allele frequency data to support medical and population genetics applications. We recruited 15,000 participants from the largest French population-based cohort, CONSTANCES, based on the birthplace proximity of their four grandparents and sent saliva kits at their homes. The high return rate (68.3%) demonstrates feasibility of large-scale self-sampling in the general population. Genotyping data from the 9,772 samples that could be processed confirm the presence of widespread fine-scale structure across France, and extend this finding to previously underrepresented regions. These results highlight the value of recruitment strategies based on grandparents’ origin for capturing subtle genetic structure. The development of sampling strategies that best capture genetic diversity at the finest scales will indeed be essential to characterize population structure across Europe and to enable more accurate analyses in medical genetics, especially when addressing rare variant interpretation and fine-scale ancestry adjustment for association tests and polygenic scores calibration. The thorough description of our recruitment strategy would provide useful insights for other initiatives like the Genome of Europe (GoE) project, which aims to generate whole-genome references encompassing European diversity.