Endocrine Abstracts

Advances in human genetics over the last two decades have discovered genes causal for thousands of monogenic conditions, characterized the mutational landscape of most forms of cancer, and identified tens of thousands of genetic variants influencing common complex traits such as diabetes and Alzheimer’s. Sequence-based diagnostics are now routinely deployed in early-onset genetic disease and in cancers, and the genetic analysis of complex traits has provided many novel and profound mechanistic insights about disease biology. Despite this, the translational impact of human genetics on late-onset disease remains limited, in part because individual variant effects are typically small. Using examples drawn from my research into the genetic basis of metabolic and endocrine disease gathered in both academia and industry, I will describe complementary approaches that are now making it possible to address this translational deficit. One involves the aggregation of genetic effects into polygenic scores that summarize individual genetic predisposition, the other the partitioning of genetic risk across diverse processes that contribute to disease pathology. These provide powerful tools for delivering increasing personalization of therapeutic care, especially when combined with non-genetic factors that also impinge on disease risk and phenotypic heterogeneity.