title: Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function.
abstract: Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.
authors.affiliation: University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, Tennessee 38163, USA.
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Siming
authors.initials: S
authors.lastname: Shou
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Qu
authors.forename: Jing
authors.initials: J
authors.lastname: Gu
authors.forename: Jintao
authors.initials: J
authors.lastname: Wang
authors.forename: Hui Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Baldwin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Langston
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Manly
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
mesh_terms: D000818:Animals; D004843:Epistasis, Genetic; D005786:Gene Expression Regulation; D006239:Haplotypes; D051379:Mice; D009424:Nervous System Physiological Phenomena; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger