Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans

View/ Open
Author
Tsaih, Shirng-Wern
Holl, Katie
Jia, Shuang
Kaldunski, Mary
Tschannen, Michael
He, Hong
Andrae, Jaime Wendt
Li, Shun-Hua
Stoddard, Alex
Wiederhold, Andrew
Parrington, John
Ruas da Silva, Margarida
Galione, Antony
Hoffmann, Raymond G.
Simpson, Pippa
Jacob, Howard
Hessner, Martin
Solberg Woods, Leah C.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1534/genetics.114.162982Metadata
Show full item recordCitation
Tsaih, S., K. Holl, S. Jia, M. Kaldunski, M. Tschannen, H. He, J. W. Andrae, et al. 2014. “Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans.” Genetics 198 (1): 17-29. doi:10.1534/genetics.114.162982. http://dx.doi.org/10.1534/genetics.114.162982.Abstract
The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174929/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347640
Collections
- HMS Scholarly Articles [17293]
Contact administrator regarding this item (to report mistakes or request changes)