Systems genetics of susceptibility to obesity-induced diabetes in mice.
Inbred strains of mice are strikingly different in susceptibility to obesity-driven diabetes. For instance, deficiency in leptin receptor (db/db) leads to hyperphagia and obesity in both C57BL/6 and DBA/2 mice, but only on the DBA/2 background do the mice develop beta-cell loss leading to severe diabetes, while C57BL/6 mice are relatively resistant. To further investigate the genetic factors predisposing to diabetes, we have studied leptin receptor-deficient offspring of an F2 cross between C57BL/6J (db/+) males and DBA/2J females. The results show that the genetics of diabetes susceptibility are enormously complex and a number of quantitative trait loci (QTL) contributing to diabetes-related traits were identified, notably on chromosomes 4, 6, 7, 9, 10, 11, 12, and 19. The Chr. 4 locus is likely due to a disruption of the Zfp69 gene in C57BL/6J mice. To identify candidate genes and to model coexpression networks, we performed global expression array analysis in livers of the F2 mice. Expression QTL (eQTL) were identified and used to prioritize candidate genes at clinical trait QTL. In several cases, clusters of eQTLs colocalized with clinical trait QTLs, suggesting a common genetic basis. We constructed coexpression networks for both 5 and 12 wk old mice and identified several modules significantly associated with clinical traits. One module in 12 wk old mice was associated with several measures of hepatic fat content as well as with other lipid- and diabetes-related traits. These results add to the understanding of the complex genetic interactions contributing to obesity-induced diabetes.
Department of Medicine, University of California, Los Angeles, California 90095-1679, USA. davisr@ucla.edu
Richard C
RC
Davis
Atila
A
van Nas
Lawrence W
LW
Castellani
Yi
Y
Zhao
Zhiqiang
Z
Zhou
Pingzi
P
Wen
Suzanne
S
Yu
Hongxiu
H
Qi
Melenie
M
Rosales
Eric E
EE
Schadt
Karl W
KW
Broman
Miklós
M
Péterfy
Aldons J
AJ
Lusis
D000818:Animals; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005821:Genetic Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008820:Mice, Obese; D046228:Microarray Analysis; D009765:Obesity / Q000150:complications* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D049490:Systems Biology / Q000379:methods