TY  - JOUR
A1  - Vogel, Heike
A1  - Kamitz, Anne
A1  - Hallahan, Nicole
A1  - Lebek, Sandra
A1  - Schallschmidt, Tanja
A1  - Jonas, Wenke
A1  - Jähnert, Markus
A1  - Gottmann, Pascal
A1  - Zellner, Lisa
A1  - Kanzleiter, Timo
A1  - Damen, Mareike
A1  - Altenhofen, Delsi
A1  - Burkhardt, Ralph
A1  - Renner, Simone
A1  - Dahlhoff, Maik
A1  - Wolf, Eckhard
A1  - Müller, Timo Dirk
A1  - Blüher, Matthias
A1  - Joost, Hans-Georg
A1  - Chadt, Alexandra
A1  - Al-Hasani, Hadi
A1  - Schürmann, Annette
T1  - A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes
JF  - Human molecular genetics
N2  - To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes.
Y1  - 2018
U6  - https://doi.org/10.1093/hmg/ddy217
SN  - 0964-6906
SN  - 1460-2083
VL  - 27
IS  - 17
SP  - 3099
EP  - 3112
PB  - Oxford Univ. Press
CY  - Oxford
ER  -