title: Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.
abstract: 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 Leptin(ob/ob) mutation (Lep(ob)). 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.
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Tu
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rabaglia
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Greenawalt
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Wang
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Bruss
authors.forename: Pek Y
authors.initials: PY
authors.lastname: Lum
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kemp
authors.forename: Christina
authors.initials: C
authors.lastname: Kendziorski
authors.forename: Brian S
authors.initials: BS
authors.lastname: Yandell
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D020738:Leptin / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese / Q000235:genetics; D060066:Protein Interaction Maps
chemical_list: D007328:Insulin; D020738:Leptin; D053829:Amyloid Precursor Protein Secretases; D005947:Glucose