The importance of context to the genetic architecture of diabetes-related traits is revealed in a genome-wide scan of a LG/J × SM/J murine model.

TitleThe importance of context to the genetic architecture of diabetes-related traits is revealed in a genome-wide scan of a LG/J × SM/J murine model.
Publication TypeJournal Article
Year of Publication2011
AuthorsLawson, HA, Lee, A, Fawcett, GL, Wang, B, L Pletscher, S, Maxwell, TJ, Ehrich, TH, Kenney-Hunt, JP, Wolf, JB, Semenkovich, CF, Cheverud, JM
JournalMamm Genome
Volume22
Issue3-4
Pagination197-208
Date Published2011 Apr
ISSN1432-1777
KeywordsAnimals, Animals, Outbred Strains, Blood Glucose, Diabetes Mellitus, Type 2, Disease Models, Animal, Female, Genome-Wide Association Study, Humans, Hybridization, Genetic, Insulin, Male, Mice, Quantitative Trait Loci
Abstract

Variations in diabetic phenotypes are caused by complex interactions of genetic effects, environmental factors, and the interplay between the two. We tease apart these complex interactions by examining genome-wide genetic and epigenetic effects on diabetes-related traits among different sex, diet, and sex-by-diet cohorts in a Mus musculus model. We conducted a genome-wide scan for quantitative trait loci that affect serum glucose and insulin levels and response to glucose stress in an F(16) Advanced Intercross Line of the LG/J and SM/J intercross (Wustl:LG,SM-G16). Half of each sibship was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (parent-of-origin imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. We found that different cohorts often have unique genetic effects at the same loci, and that genetic signals can be masked or erroneously assigned to specific cohorts if they are not considered individually. Our data demonstrate that the effects of genes on complex trait variation are highly context-dependent and that the same genomic sequence can affect traits differently depending on an individual's sex and/or dietary environment. Our results have important implications for studies of complex traits in humans.

DOI10.1007/s00335-010-9313-3
Alternate JournalMamm. Genome
PubMed ID21210123
PubMed Central IDPMC3650899
Grant ListT32 HL091823 / HL / NHLBI NIH HHS / United States
P30 DK056341 / DK / NIDDK NIH HHS / United States
T32-HL091823 / HL / NHLBI NIH HHS / United States
BB/C/516936 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/C516936/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 DK055736 / DK / NIDDK NIH HHS / United States
R01 DK088083 / DK / NIDDK NIH HHS / United States
P30 DK056341-11 / DK / NIDDK NIH HHS / United States