Filling in the Missing Heritability of Complex Disease: Exome Sequencing Identifies DNPEP as a Novel Potential Risk Gene for Type 2 Diabetes

Abstract

Although over 70 susceptibility loci for type 2 diabetes (T2D) have been identified through genome-wide association studies, a large proportion of T2D heritability remains unexplained. Recent evidence suggests that rare variants, with frequencies too low to be detected through current genome-wide approaches, may contribute substantially to complex disease. The present study involved exome sequencing of an atypical pre-diabetic subject and her unaffected family members. The subject had none of the common risk factors for T2D, suggesting a genetic component may be involved and thus provided an opportunity for exploring the genetic architecture of T2D and the potential role of rare variants. This study resulted in the identification of DNPEP as a potential new risk gene for T2D and a homozygous deleterious variant in this gene as the most likely genetic variant predisposing the subject to pre-diabetes. This hypothesis is strongly supported by unpublished data showing that DNPEP knockout mice exhibit a clearly diabetic phenotype. The current study results also suggest a potential personalized treatment option for the subject that could specifically counteract the effects of decreased DNPEP function. Candidate variants with potential relevance to the subject’s pre-diabetic condition were identified in six additional genes. Each of these mutations is found at an exceptionally low frequency in the population databases, providing support for the rare-variant hypothesis of common disease. In addition, although the cost of genome sequencing has fallen dramatically in recent years, the integration of this information into routine health care remains debated. The results of the present study shed light on the difficulties of interpreting genomic data given limited knowledge of human gene function and suggest that genome sequencing in generally healthy individuals may be of limited utility at the current time.