Genetics of Type 2 Diabetes

Excerpt

Since early 2007, the establishment of international consortia and biobanks has catalyzed the performance of large-scale genomic studies. These efforts have driven an explosion in the discovery of genetic variation associated with type 2 diabetes. Most studies have involved genetic data captured using genotyping arrays populated by common single nucleotide polymorphisms (SNPs), although a rapid drop in the cost of next-generation sequencing has facilitated a growing number of exome and genome sequencing studies, which can capture increasingly rare variation. Hundreds of independent SNPs have been associated with type 2 diabetes and glycemic traits using genome-wide association studies (GWAS), and their numbers continue to increase. Findings have pointed to both known and novel molecular pathways and increased the understanding of fundamental disease biology.

On the other hand, causal variants have been identified for only a small fraction of the loci identified by GWAS, and a substantial proportion of disease heritability remains unexplained. While combining genetic variation into polygenic scores improves prediction of type 2 diabetes risk substantially beyond that of single variants, such scores are not yet used in clinical practice due to inadequate predictive ability and implementation challenges. Despite including millions of individuals, genetic studies remain limited by the diversity of populations represented, are underpowered to fully capture rare variation of modest effect sizes, and have incomplete ascertainment of alternate (non-SNP) forms of genetic variation.

As the community continues to expand genetic discovery and pursues systematic fine-mapping, platforms that focus on functional variation, systems biology approaches, and expansion to non-European populations, the coming years will witness exponential growth in our understanding of the genetic architecture of metabolic phenotypes related to type 2 diabetes. Whether these findings prove useful in disease prediction or therapeutic decision-making must be tested in rigorously designed clinical trials.