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Genetics. 2018 Dec;210(4):1527-1542. doi: 10.1534/genetics.118.301578. Epub 2018 Oct 19.

Two Novel Candidate Genes for Insulin Secretion Identified by Comparative Genomics of Multiple Backcross Mouse Populations.

Author information

1
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Medical Faculty, Heinrich Heine University, D-40225 Duesseldorf, Germany.
2
German Center for Diabetes Research (DZD), D-85764 München-Neuherberg, Germany.
3
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
4
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, D-14558 Nuthetal, Germany.
5
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Medical Faculty, Heinrich Heine University, D-40225 Duesseldorf, Germany alexandra.chadt@ddz.uni-duesseldorf.de hadi.al-hasani@ddz.uni-duesseldorf.de.

Abstract

To identify novel disease genes for type 2 diabetes (T2D) we generated two backcross populations of obese and diabetes-susceptible New Zealand Obese (NZO/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Subsequent whole-genome linkage scans revealed 30 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose [12 cM, logarithm of the odds (LOD) 13.3] and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Nbg7p, NZO blood glucose on proximal chromosome 7) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is contributed by the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains and metabolic phenotyping validated the phenotype. For the detection of candidate genes in the critical region (30-46 Mb), we used a combined approach of haplotype and gene expression analysis to search for C3H-specific gene variants in the pancreatic islets, which appeared to be the most likely target tissue for the QTL. Two genes, Atp4a and Pop4, fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to decreased glucose-stimulated insulin secretion, indicating a regulatory role of both genes in insulin secretion, thereby possibly contributing to the phenotype linked to Nbg7p In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility candidate genes, and thus has been proven to be a valuable tool for the discovery of novel disease genes.

KEYWORDS:

candidate disease genes; diabetes; haplotypes; positional cloning; quantitative trait loci

PMID:
30341086
PMCID:
PMC6283180
[Available on 2019-12-01]
DOI:
10.1534/genetics.118.301578
[Indexed for MEDLINE]

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