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

Author:

Tsaih Shirng-Wern1,Holl Katie12,Jia Shuang12,Kaldunski Mary12,Tschannen Michael1,He Hong12,Andrae Jaime Wendt1,Li Shun-Hua2,Stoddard Alex12,Wiederhold Andrew2,Parrington John3,Ruas da Silva Margarida3,Galione Antony3,Meigs James4,Hoffmann Raymond G12,Simpson Pippa12,Jacob Howard12,Hessner Martin12,Solberg Woods Leah C12,

Affiliation:

1. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

2. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

3. Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, United Kingdom

4. Department of Medicine, Harvard Medical School, General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts 02114

Abstract

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.

Publisher

Oxford University Press (OUP)

Subject

Genetics

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