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A meta-analysis of QTL for diabetes-related traits in rodents

¹ Department of Pharmacology, German Institute for Human Nutrition Potsdam-Rehbrücke, Nuthetal
² Department of Epidemiology, German Institute for Human Nutrition Potsdam-Rehbrücke, Nuthetal
³ Microdiscovery GmbH, Berlin, Germany

Crossbreeding studies in rodents have identified numerous quantitative trait loci (QTL) that are linked to diabetes-related component traits. To identify genetic consensus regions implicated in insulin action and glucose homeostasis, we have performed a meta-analysis of genomewide linkage scans for diabetes-related traits. From a total of 43 published genomewide scans we assembled a nonredundant collection of 153 QTL for glucose levels, insulin levels, and glucose tolerance. Collectively, these studies include data from 48 different parental strains and >11,000 individual animals. The results of the studies were analyzed by the truncated product method (TPM). The analysis revealed significant evidence for linkage of glucose levels, insulin levels, and glucose tolerance to 27 different segments of the mouse genome. The most prominent consensus regions [localized to chromosomes 2, 4, 7, 9, 11, 13, and 19; logarithm of odds (LOD) scores 10.5–17.4] cover 11% of the mouse genome and collectively contain the peak markers for 47 QTL. Approximately half of these genomic segments also show significant linkage to body weight and adiposity, indicating the presence of multiple obesity-dependent and -independent consensus regions for diabetes-related traits. At least 84 human genetic markers from genomewide scans and >80 candidate genes from human and rodent studies map into the mouse consensus regions for diabetes-related traits, indicating a substantial overlap between the species. Our results provide guidance for the identification of novel candidate genes and demonstrate the presence of numerous distinct consensus QTL regions with highly significant LOD scores that control glucose homeostasis. An interactive physical map of the QTL is available online at http://www.diabesitygenes.org.

diabesity; genomewide scan; hidden Markov model; quantitative trait loci; truncated product method