Philippe Froguel

Fine-scale human genetic structure in Western France

The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.

Maturity-Onset Diabetes of the Young: From Genetics to Translational Biology and Personalized Medicine

Monogenic diabetes is defined as diabetes resulting from a rare causal deleterious mutation of a single gene that usually impairs pancreatic β-cell function. There is a large spectrum of clinical presentations of monogenic diabetes, depending on the affected gene and the nature of the mutation. Maturity-onset diabetes of the young (MODY) is the most frequent, representing 1-2% of all diabetes cases. MODY is dominantly inherited with early-onset nonautoimmune diabetes. At least 14 MODY genes have been identified so far, including key genes involved in developmental and/or functional processes of the pancreatic β-cell physiology. These discoveries remarkably modified patients care, improving their quality of life and long-term evolution, and offer proof-of-concepts of successful genomic diabetes medicine. Further, recent advances in genome editing and pluripotent stem-cell reprogramming technologies are providing new opportunities and challenges for in vitro human cell-based diabetes modelling and for novel drugs and cell-based diabetes therapy discovery.This review chapter focuses on the lessons learned from MODY gene identification to clinical translational research and implementation of personalized genomic medicine, as well as on future directions to further elucidate and better understand the pathophysiological mechanisms underlying early-onset monogenic diabetes.

Historical Overview of Gene Discovery Methodologies in Type 2 Diabetes

This initial chapter presents a historical snapshot of the various approaches utilized to discover genes implicated in the pathogenesis of type 2 diabetes.