Phd in HUMAN BIOLOGY AND MEDICAL GENETICS

Thesis title: Role of monogenic diabetes genes on age at onset of type 2 diabetes mellitus

The rising prevalence of type 2 diabetes (T2D) among young adults is alarming because of the increased risk of cardiovascular complications in early-onset T2D patients. Both rare and common variants shape the risk of T2D. The role of such variants on disease anticipation is unknown. 600 individuals with age at T2D onset <35 (n=300, cases) or >65 (n=300, controls) years, selected from a total of 9,712 patients were investigated to study whether rare (minor allele frequency, MAF, <1%) and possibly deleterious (i.e. with an estimated impact on protein function) variants from 27 monogenic diabetes-genes and/or common T2D susceptibility SNPs play a role on the risk of early-onset diabetes. Rare variants considered together significantly increased by 64% the risk of early-onset T2D. This enrichment was progressively greater in classes of progressively rarer allele, culminating to more than a 6.5-fold increase for ultra-rare variants (MAF<0.001%). One unit of a genetic score based on T2D-SNPs significantly increased by 9% the risk of early-onset disease. Getting further insights into genetic background shaping the risk of early-onset T2D is part of a general attempt aimed at predicting and possibly preventing the anticipation of T2D.