TY - JOUR
T1 - Integrative Analysis of a Cross-Loci Regulation Network Identifies App as a Gene Regulating Insulin Secretion from Pancreatic Islets
AU - Tu, Zhidong
AU - Keller, Mark P.
AU - Zhang, Chunsheng
AU - Rabaglia, Mary E.
AU - Greenawalt, Danielle M.
AU - Yang, Xia
AU - Wang, I. Ming
AU - Dai, Hongyue
AU - Bruss, Matthew D.
AU - Lum, Pek Y.
AU - Zhou, Yun Ping
AU - Kemp, Daniel M.
AU - Kendziorski, Christina
AU - Yandell, Brian S.
AU - Attie, Alan D.
AU - Schadt, Eric E.
AU - Zhu, Jun
PY - 2012/12
Y1 - 2012/12
N2 - Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptinob/ob mutation (Lepob). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.
AB - Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptinob/ob mutation (Lepob). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=84872041117&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1003107
DO - 10.1371/journal.pgen.1003107
M3 - Article
C2 - 23236292
AN - SCOPUS:84872041117
SN - 1553-7390
VL - 8
JO - PLoS Genetics
JF - PLoS Genetics
IS - 12
M1 - e1003107
ER -