Sequencing approaches to type 2 diabetes

Abstract

Rapid advancement and decreasing costs of DNA sequencing technologies have yielded great strides in improving our understanding of the genetic etiology of human disease, including type 2 diabetes (T2D). The state of the science of sequencing in human disease has progressed from being largely restricted to single-gene disorders, to elucidating common variants conferring susceptibility to common diseases, and most recently to the cataloging of rare variants involved in common diseases. Sanger sequencing, DNA amplification, and microarrays provided early insights into the genetic architecture of type 2 diabetes, but the establishment of massively parallel sequencing platforms has accelerated the process. There are several different platforms, including Illumina, Pacific Biosciences, and Ion Torrent technologies. Each platform has its own specific strengths and weakness, and proper quality control and variant-calling techniques are crucial for accurate sequencing data. The high-throughput capabilities of these technologies have allowed population-based sequencing projects, such as the 1000 Genomes Project, to create repositories of human genomic variation. Genetic variants first associated with T2D were discovered through sequencing a number of candidate genes, with PPARG and KCNJ11 yielding variants with consistent enough association to be established universally as the first two T2D susceptibility genes. Variants in the HNF4A pancreatic-specific P2 promoter and TCF7L2 gene were both discovered through sequencing of linkage signals. Genome-wide association studies have found many T2D-associated regions, but a limited amount of sequencing has been performed to follow up these studies with limited numbers of causal variants being discovered. The growth of massively parallel sequencing has led to the generation of comprehensive sequencing across the exome and genome of large numbers of individuals with T2D in projects such as the T2D-GENES consortium. These data will provide the enhanced understanding of the genetic architecture of T2D necessary for improving approaches to the prevention and treatment of T2D.