Faculty Collaboration Database

Identification of a novel gene for diabetic traits in rats, mice, and humans. Genetics 2014 Sep;198(1):17-29

Date

09/23/2014

Pubmed ID

25236446

Pubmed Central ID

PMC4174929

DOI

10.1534/genetics.114.162982

Scopus ID

2-s2.0-84907982004 (requires institutional sign-in at Scopus site)   36 Citations

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.

Author List

Tsaih SW, Holl K, Jia S, Kaldunski M, Tschannen M, He H, Andrae JW, Li SH, Stoddard A, Wiederhold A, Parrington J, Ruas da Silva M, Galione A, Meigs J, Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) Investigators, Hoffmann RG, Simpson P, Jacob H, Hessner M, Solberg Woods LC

Authors

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Glucose
Calcium Channels
Diabetes Mellitus, Type 2
Female
Genome, Human
Humans
Insulin
Male
Mice
Mice, Inbred C57BL
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Rats
Rats, Inbred Strains