University of Tennessee-Memphis Genetic correlations and associative networks for CNS transcript abundance and neurobehavioral phenotypes in a recombinant inbred mapping panel Elissa J. Chesler, Jintao Wang, Lu Lu, Jeremy L. Peirce, Yanhua Qu, Kenneth F. Manly, Robert W. Williams University of Tennessee-Memphis Health Science Center

Genetic Correlations: Relation of trait values in genetically similar individuals Which traits share a common genetic mediation? (Genetic Correlations) Which genes have expression levels associated with the trait? Where are the polymorphisms that influence the traits? (Trait to Marker Correlations - Quantitative Trait Loci)

BXD Recombinant Inbred Strains Several hundred phenotypes have been studied ( > 500 ). Brain expression of several thousand genes have been measured using Affymetrix microarrays. 750+ genetic marker strain distributions are known. All data is available at www.webqtl.org No additional genotyping is necessary to perform genetic analyses.

Search the BXD Published Phenotypes and Gene Expression Databases at www.webqtl.org Affymetrix Gene Expression Data in BXD RI mice

Marker-Trait Associations DBA/2J C57BL/6J

Drd2 expression is determined by genetic variation near the transcript

Correlations of Drd2 expression with published phenotypes Negative correlation with activity Positive correlation with conditioned place preference and other consumption

Re-mapping a published phenotype N = 20 strains

Genes that correlate with ethanol conditioned place preference

The same polymorphism controlling Drd2 expression may regulate EtOH induced CPP and OFA Conditioned Place Preference Phenotyping a larger set of BXD mice will increase statistical power for QTL detection and trait association EtOH Open Field Activity

Pleiotropy or Linkage? r = -.68 r = -.24 r = 0.65 r = .73 Gene 1 Trait 1 Trait 1 Gene 1 Trait 2 Gene 2 Trait 2 Kcnj9 Chr 1 @ 173.612 Mb Sdhc Chr 1 @ 172.407 Mb r = -.68 r = -.24 Ethanol Acceptance (Female) r = 0.65 r = .73 Tolerance to Ethanol Ataxia

Linking In and Out From WebQTL UTHSC GENE EXPRESSION DATA LOCUS LINK SCATTER PLOTS UCSC GENOME BROWSER Pub MED PUBLISHED PHENOTYPES DATABASE

SNPs in the untranslated region near Drd2 Several SNPs Are Within 4 KB of Drd2 Flanking SNPs

Building Association Networks for Transcripts and Behavior

Relational Genetic Analysis Using RI Strains As more traits are added the utility of this resource grows multiplicatively

Acknowledgements University of Tennessee Health Science Center Dr. Robert Williams Dr. Lu Lu Dr. Siming Shou Dr. Yan Hua Qu Roswell Park Cancer Institute - WebQTL Dr. Kenneth Manly Jintao Wang Oregon Health Sciences University Dr. John Crabbe Dr. John Belknap -Human Brain Project funded jointly by the NIMH, NIDA, and the NSF -The National Institute on Alcohol Abuse and Alcoholism (INIA grants U01AA13499, U24AA13513 to RW)

Complete tutorial at www.WebQTL.org

High density Marker Map for Re-analysis of BXD Phenotypes The marker map used for BXD RI expression QTL mapping. The current map has ~750 markers Pair-wise recombination fractions (upper triangle) and LOD scores for linkage of markers (lower triangle). Warmer colors indicate greater linkage. Plots were created using R/QTL.

Correlation Analysis Options and Diagnostic Plots Evaluating Linearity and Univariate Normality

Gene expression correlates with the corticosterone release response to ethanol

Trait to trait correlations – Several system-wide traits affected by chronic corticosterone elevation

University of Tennessee-Memphis Web-Based QTL Mapping and Genetic Correlation Analysis of Gene Expression and Alcohol-Related Traits in BXD Strains Elissa J. Chesler, Jintao Wang, Lu Lu, Jeremy L. Peirce, Yanhua Qu, Kenneth F. Manly, Robert W. Williams University of Tennessee-Memphis Health Science Center