Download Genetic correlations and associative networks for CNS transcript

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
BEHAVIOR
(Genetic Correlations)
• Where are the
polymorphisms that
influence the traits?
(Trait to Marker Correlations Quantitative Trait Loci)
L6
BX J
D
BX 1
D
BX 5
BX D8
D
BX 1 1
D
BX 1 3
D
BX 1 5
D
BX 1 8
D
BX 2 2
D
BX 2 5
D
BX 2 8
D
BX 3 1
D
BX 3 3
D4
0
F1
mRNA LEVEL
9.8
9.6
9.4
9.2
9
8.8
8.6
8.4
L6
BX J
D
BX 1
D
BX 5
BX D8
D
BX 1 1
D
BX 1 3
D
BX 1 5
D
BX 1 8
D
BX 2 2
D
BX 2 5
D
BX 2 8
D
BX 3 1
D
BX 3 3
D4
0
F1
• Which genes have
expression levels
associated with the
trait?
C5
7B
(Genetic Correlations)
80
75
70
65
60
55
50
45
C5
7B
• Which traits share a
common genetic
mediation?
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.
female
female
C57BL/6J
C57BL/6J (B)
(B)
fully
fully
inbred
inbred
male
male
DBA/2J
DBA/2J (D)
(D)
BXD
chromosome
chromosome pair
pair
isogenic
isogenic
F1
heteroheterogeneous
geneous
F2
Inbred
Inbred
Isogenic
Isogenic
siblings
siblings
20
20 generations
generations
Recombined
Recombined
chromosomes
chromosomes
are
are needed
needed for
for
mapping
mapping
BXD
BXD RI
RI
Strain
Strain set
set
BXD1
BXD1
brother-sister
brother-sister
matings
matings
BXD2
BXD2
+…+
BXD80
BXD80
Search the BXD Published Phenotypes and
Gene Expression Databases at www.webqtl.org
Affymetrix Gene
Expression Data
in BXD RI mice
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.
Marker-Trait
Associations
DBA/2J
C57BL/6J
Correlation Analysis Options
and Diagnostic Plots
Evaluating Linearity and Univariate Normality
Drd2 expression is determined by
genetic variation near the transcript
Correlations of Drd2 expression with
published phenotypes
ETOH_CPP
SACCPREF
ETOH_OFA
ETOH_PREF
LOCACT
MORPREF ETOHCPPSHK
DRD2
ETOH_CPP
SACCPREF
ETOH_OFA
ETOH_PREF
LOCACT
MORPREF ETOHCPPSHK
DRD2
DRD2
DRD2
ETOH_CPP
ETOH_CPP
ETOH_OFA ETOH_PREF
ETOH_PREF ETOH_OFA SACCPREF
SACCPREF
LOCACT
LOCACT
ETOHCPPSHK MORPREF
Positive correlation with
conditioned place preference and
other consumption
MORPREF ETOHCPPSHK
Negative correlation with activity
Re-mapping a
published
phenotype
N = 20
strains
Genes that correlate with ethanol
conditioned place preference
PSMC2
ITM1
UBE2N
HTR2C
AI847581
HNRPK
EIF2S2
ETOH_CPP
DRD2
DPM1
CCT6A
UBE2N
UBE2N
ITM1
ITM1
PSMC2
PSMC2
ETOH_CPP
CCT6A
DRD2
DPM1
DPM1
DRD2
CCT6A
ETOH_CPP
EIF2S2
EIF2S2
HNRPK
HNRPK
AI847581
AI847581
HTR2C
HTR2C
ETOH_CPP
DRD2
DPM1
CCT6A
PSMC2
ITM1
UBE2N
HTR2C
AI847581
HNRPK
EIF2S2
Pearson r Influence
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
The same
polymorphism
controlling
Drd2
Drd2
expression
may regulate
EtOH induced
CPP and OFA
Phenotyping a larger set
of BXD mice will increase
statistical power for QTL
detection and trait
association
Conditioned
Place
Preference
EtOH
Open Field
Activity
Pleiotropy or Linkage?
Trait 1
Gene
1
Trait 2
Kcnj9
Chr 1 @ 173.612 Mb
r = -.68
Ethanol
Acceptance
(Female)
r = 0.65
Tolerance
to Ethanol
Ataxia
Gene
1
Trait 1
Gene
2
Trait 2
Sdhc
Chr 1 @ 172.407 Mb
r = -.24
r = .73
Linking In and Out From WebQTL
UTHSC GENE
EXPRESSION
DATA
LOCUS
LINK
SCATTER
PLOTS
Pub
MED
PUBLISHED
PHENOTYPES
DATABASE
UCSC
GENOME
BROWSER
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
Complete tutorial at www.WebQTL.org
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)