Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function

Elissa J. Chesler, Lu Lu, Siming Shou, Yanhua Qu, Jing Gu, Jintao Wang, Hui Chen Hsu, John D. Mountz, Nicole E. Baldwin, Michael A. Langston, David W. Threadgill, Kenneth F. Manly, Robert Williams

Research output: Contribution to journalArticle

528 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)233-242
Number of pages10
JournalNature Genetics
Volume37
Issue number3
DOIs
StatePublished - Dec 9 2005

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Nervous System
Quantitative Trait Loci
Gene Expression
Oligonucleotide Array Sequence Analysis
Base Pairing
Synapses
Haplotypes
Single Nucleotide Polymorphism
Central Nervous System
Databases
Pharmacology
Phenotype
Population
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. / Chesler, Elissa J.; Lu, Lu; Shou, Siming; Qu, Yanhua; Gu, Jing; Wang, Jintao; Hsu, Hui Chen; Mountz, John D.; Baldwin, Nicole E.; Langston, Michael A.; Threadgill, David W.; Manly, Kenneth F.; Williams, Robert.

In: Nature Genetics, Vol. 37, No. 3, 09.12.2005, p. 233-242.

Research output: Contribution to journalArticle

Chesler, EJ, Lu, L, Shou, S, Qu, Y, Gu, J, Wang, J, Hsu, HC, Mountz, JD, Baldwin, NE, Langston, MA, Threadgill, DW, Manly, KF & Williams, R 2005, 'Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function', Nature Genetics, vol. 37, no. 3, pp. 233-242. https://doi.org/10.1038/ng1518
Chesler, Elissa J. ; Lu, Lu ; Shou, Siming ; Qu, Yanhua ; Gu, Jing ; Wang, Jintao ; Hsu, Hui Chen ; Mountz, John D. ; Baldwin, Nicole E. ; Langston, Michael A. ; Threadgill, David W. ; Manly, Kenneth F. ; Williams, Robert. / Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. In: Nature Genetics. 2005 ; Vol. 37, No. 3. pp. 233-242.
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