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dc.contributor.authorTsaih, Shirng-Wernen_US
dc.contributor.authorHoll, Katieen_US
dc.contributor.authorJia, Shuangen_US
dc.contributor.authorKaldunski, Maryen_US
dc.contributor.authorTschannen, Michaelen_US
dc.contributor.authorHe, Hongen_US
dc.contributor.authorAndrae, Jaime Wendten_US
dc.contributor.authorLi, Shun-Huaen_US
dc.contributor.authorStoddard, Alexen_US
dc.contributor.authorWiederhold, Andrewen_US
dc.contributor.authorParrington, Johnen_US
dc.contributor.authorRuas da Silva, Margaridaen_US
dc.contributor.authorGalione, Antonyen_US
dc.contributor.authorMeigs, Jamesen_US
dc.contributor.authorHoffmann, Raymond G.en_US
dc.contributor.authorSimpson, Pippaen_US
dc.contributor.authorJacob, Howarden_US
dc.contributor.authorHessner, Martinen_US
dc.contributor.authorSolberg Woods, Leah C.en_US
dc.date.accessioned2014-11-03T17:40:41Z
dc.date.issued2014en_US
dc.identifier.citationTsaih, 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.en
dc.identifier.issn0016-6731en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13347640
dc.description.abstractThe 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.en
dc.language.isoen_USen
dc.publisherGenetics Society of Americaen
dc.relation.isversionofdoi:10.1534/genetics.114.162982en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174929/pdf/en
dash.licenseLAAen_US
dc.subjecten
dc.subjectheterogeneous stock ratsen
dc.subjectexpression QTL mappingen
dc.subjecttype 2 diabetesen
dc.subjectglucoseen
dc.subjectinsulinen
dc.subjectMultiparent Advanced Generation Inter-Cross (MAGIC)en
dc.subjectmultiparental populationsen
dc.subjectMPPen
dc.subjectgene mappingen
dc.titleIdentification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humansen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalGeneticsen
dash.depositing.authorMeigs, Jamesen_US
dc.date.available2014-11-03T17:40:41Z
dc.identifier.doi10.1534/genetics.114.162982*
dash.authorsorderedfalse
dash.contributor.affiliatedMeigs, James


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