genetic correlations: relation of trait values in genetically similar individuals
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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-MemphisHealth 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?
(Genetic Correlations)
• Where are the polymorphisms that influence the traits?
(Trait to Marker Correlations - Quantitative Trait Loci)
BEHAVIOR
45
50
55
60
65
70
75
80
mRNA LEVEL
8.4
8.6
8.8
9
9.2
9.4
9.6
9.8
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.
C57BL/6J (B)C57BL/6J (B) DBA/2J (D)DBA/2J (D)
F1F1
20 generations
brother-sister
matings
20 generations
brother-sister
matings
BXD1BXD1 BXD2BXD2 BXD80BXD80+ … ++ … +
F2F2
BXD RIStrain setBXD RI
Strain set
fullyinbredfully
inbred
isogenicisogenic
hetero-geneoushetero-
geneous
Recombined chromosomes are needed for
mapping
Recombined chromosomes are needed for
mapping
femalefemale malemale
chromosome pairchromosome pair
InbredIsogenicsiblings
InbredIsogenicsiblings
BXDBXD
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.
C57BL/6J
DBA/2JMarker-Trait Associations
Correlation Analysis Options and Diagnostic Plots
Evaluating Linearity and Univariate Normality
Drd2 expression is determined by genetic variation near the
transcript
DRD2
DR
D2
ETOH_CPP SACCPREF ETOH_OFA ETOH_PREF LOCACT MORPREF ETOHCPPSHK
DR
D2
ET
OH
_CP
P
ET
OH
_CP
P
SA
CC
PR
EF
SA
CC
PR
EF
ET
OH
_OF A
ET
OH
_OFA
ET
OH
_PR
EF
ET
OH
_PR
EF
L OC
AC
T
LOC
AC
T
MO
RP
RE
F
MO
RP
RE
F
DRD2
ET
OH
CP
PS
HK
ETOH_CPP SACCPREF ETOH_OFA ETOH_PREF LOCACT MORPREF ETOHCPPSHK
ET
OH
CP
PS
HK 0.00
0.010.020.030.040.050.060.070.080.090.10
Pearson r Influence
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
ETOH_CPP
ET
OH
_CP
P
DRD2 DPM1 CCT6A PSMC2 ITM1 UBE2N HTR2C AI847581 HNRPK EIF2S2
ET
OH
_CP
P
DR
D2 D
RD
2
DP
M1
DP
M1
CC
T6A
CC
T6A
PS
MC
2
PS
MC
2
ITM
1
ITM
1
UB
E2 N
UB
E2N
HT
R2C
HT
R2C
AI 8
4758
1
AI847581
HN
RP
K
HN
RP
K
ETOH_CPP
EIF
2S2
DRD2 DPM1 CCT6A PSMC2 ITM1 UBE2N HTR2C AI847581 HNRPK EIF2S2
EIF
2S2
0.000.010.020.030.040.050.060.070.080.090.10
Pearson r Influence
Genes that correlate with ethanol conditioned place preference
Phenotyping a larger set of BXD mice will increase statistical power for QTL detection and trait association
Drd2
Conditioned Place Preference
The same polymorphism controlling Drd2 expression may regulate EtOH induced CPP and OFA
EtOH Open Field Activity
Kcnj9Chr 1 @ 173.612 Mb
SdhcChr 1 @ 172.407 Mb
Ethanol Acceptance
(Female)
Tolerance to Ethanol
Ataxia
Pleiotropy or Linkage?
Trait 1
Trait 2
Trait 1
Trait 2
Gene 1
Gene 2
Gene 1
r = -.68
r = .73
r = -.24
r = 0.65
Linking In and Out From WebQTL
UTHSC GENE
EXPRESSION DATA
LOCUS LINK
Pub MED
UCSC GENOME
BROWSER
PUBLISHED PHENOTYPES DATABASE
SCATTER PLOTS
SNPs in the untranslated region near Drd2
Flanking SNPs
Several SNPs Are Within 4 KB of Drd2
72+++Pak3 bindinprotein
70+4@100D 13@90D19@10B
Prss15Chr17@56
Protease, serine 15
9.26.9
69+++4@60D13@90D
AA536646Chr4 @13810.08.5
80
69+++4@55D 6@100D9@65B
Akt2Chr7 @20
v-aktmurinethymomaviral protooncogene2
10.88.8
85
68+
6@95D 9@65B 12@85D X@15D
CrhrChr11 @105
corticotropinreleasing hormone receptor
9.37.6
88
65+++2@135D4@60D13@85D
BlcapChr2@158
bladder cancer associated protein
10.48.486
71+++4@60D13@85D
Kifc2Chr15@77
kinesinfamily member C2
8.97.2
71+++
4@60D13@85D
Kcnab2Chr4@148
potassium voltage-gated channel, shaker related beta 2
8.97.2
84
71+++4@60D13@85D
AF100956Chr17@33
10.79.789
71+++4@60D13@85D
Hcn2Chr10@80
hyperpolarization-activated cyclicnuceotide-gatedpottasiumm2
10.79.7
88
72+++4@60D9@60B11@80D 13@90D
Akt1Chr12@107
thymonaviral protooncogene1
11.010.1
88
71+++
71++
4@65D13@85D
Brd4Chr17 @31
bromodomain4
10.07.5
87
71+++4@65D13@85D18@80B
MtsskChr4@114
microtubleassociated testis specific serine/threonine kinase
10.07.5
8787
84
85
74+++
4@65D 5@110B 6@25D 13@85D
Prss25Chr6@84
Protease, serine 25
9.36.9
83
70+++4@60D 13@90D19@50D X@10D
Igfbp6Chr15@103
insulin like growth factor binding protein 6
10.89.0
8390
86
85
70+++3@150D 4@65D13@85D 19@40
2600002E23Rik
Chr4@128
9.98.5
Peflin86
84
8671+++4@60D13@90D19@35D
Chr15@77
cysteineandhistidinerich protein
10.89.0
Cyhr1
87
83
4@60D6@100D 13@95D X@15D
Scamp3Chr3 @9010.48.7
secretorycarrier membrane protein 3
-74
79
-81w
77 59+-2@5B4@140B 5@95B 9@60B
Drd2
66+-
2@5D3@50D 4@140D 9@6510@35D 12@100B 15@10D X@5B
AU044290
69+-8@35D9@55B
0610010I23Rik74
4@115D4@140D5@95D 9@100D
C85523-73
61+-4@10D5@90B 9@60B 17@55D
Chr15@81
11.911.2
Cbx6
72+-4@10D4@60D 5@95B 9@45B
Ntsr2
73 73neurotensinreceptor 2
77+-9@60B12@100D19@50DX@60
AW124133
73+++
9@65D12@65B17@55B
C76439
65+-2@5B 9@459@65X@10D
Ramp2
69
-69
69
Crip2
79
73
75
-77
81chromobox homolog6
72
71
hippocampus 38.5kDa
83 72+-4@10D4@45D 19@45D X@80D
Slc9a3r1
sodium/hydrogen exchangerisoform3regulator 1
86
XX+-4@XXD5@90B 9@60B 17@55D
Chr4@138
1X.911.2
Casp9
caspase9AI115399
86++++
9@65D12@[email protected]
Tceb1
transcription elongationfactor B 1
84
76 63+-1@95B 5@50B12@45B
Casp3
caspase3, apoptosisrelatedcysteineprotease
-69
-72
xx
79
dopamine receptor D2
receptor activitymodifyingprotein 2cysteinerich protein 2
4@60D6@100D 13@95D X@15D
Scamp3Chr3 @9010.48.7
secretorycarrier membraneprotein 3
Ethanol-induced conditioned place preference
742@5B4@100B7@95B 8@7518@15D
Chr13 @ 85 Mb
Chr2 @ 5 Mb
Chr9 @ 65 Mb
68+-1@175D4@65B
Chr12@39
Dnaj homologsubfamiyB9
11.010.1
Dnajb9
56+-74+++
72+++Pak3 bindinprotein
70+4@100D 13@90D19@10B
Prss15Chr17@56
Protease, serine 15
9.26.9
70+4@100D 13@90D19@10B
Prss15Chr17@56
Protease, serine 15
9.26.9
69+++4@60D13@90D
AA536646Chr4 @13810.08.5
69+++4@60D13@90D
AA536646Chr4 @13810.08.5
80
69+++4@55D 6@100D9@65B
Akt2Chr7 @20
v-aktmurinethymomaviral protooncogene2
10.88.8
69+++4@55D 6@100D9@65B
Akt2Chr7 @20
v-aktmurinethymomaviral protooncogene2
10.88.8
85
68+
6@95D 9@65B 12@85D X@15D
CrhrChr11 @105
corticotropinreleasing hormone receptor
9.37.6
68+
6@95D 9@65B 12@85D X@15D
CrhrChr11 @105
corticotropinreleasing hormone receptor
9.37.6
88
65+++2@135D4@60D13@85D
BlcapChr2@158
bladder cancer associated protein
10.48.486
71+++4@60D13@85D
Kifc2Chr15@77
kinesinfamily member C2
8.97.2
71+++4@60D13@85D
Kifc2Chr15@77
kinesinfamily member C2
8.97.2
71+++
4@60D13@85D
Kcnab2Chr4@148
potassium voltage-gated channel, shaker related beta 2
8.97.2
71+++
4@60D13@85D
Kcnab2Chr4@148
potassium voltage-gated channel, shaker related beta 2
8.97.2
84
71+++4@60D13@85D
AF100956Chr17@33
10.79.7
71+++4@60D13@85D
AF100956Chr17@33
10.79.789
71+++4@60D13@85D
Hcn2Chr10@80
hyperpolarization-activated cyclicnuceotide-gatedpottasiumm2
10.79.7
88
72+++4@60D9@60B11@80D 13@90D
Akt1Chr12@107
thymonaviral protooncogene1
11.010.1
72+++4@60D9@60B11@80D 13@90D
Akt1Chr12@107
thymonaviral protooncogene1
11.010.1
88
71+++
71++
4@65D13@85D
Brd4Chr17 @31
bromodomain4
10.07.5
87
71+++4@65D13@85D18@80B
MtsskChr4@114
microtubleassociated testis specific serine/threonine kinase
10.07.5
8787
84
85
74+++
4@65D 5@110B 6@25D 13@85D
Prss25Chr6@84
Protease, serine 25
9.36.9
83
70+++4@60D 13@90D19@50D X@10D
Igfbp6Chr15@103
insulin like growth factor binding protein 6
10.89.0
8390
86
85
70+++3@150D 4@65D13@85D 19@40
2600002E23Rik
Chr4@128
9.98.5
Peflin70+++
3@150D 4@65D13@85D 19@40
2600002E23Rik
Chr4@128
9.98.5
Peflin86
84
8671+++4@60D13@90D19@35D
Chr15@77
cysteineandhistidinerich protein
10.89.0
Cyhr1
87
83
4@60D6@100D 13@95D X@15D
Scamp3Chr3 @9010.48.7
secretorycarrier membrane protein 3
-74
79
-81w
77 59+-2@5B4@140B 5@95B 9@60B
Drd2
66+-
2@5D3@50D 4@140D 9@6510@35D 12@100B 15@10D X@5B
AU044290
69+-8@35D9@55B
0610010I23Rik74
4@115D4@140D5@95D 9@100D
C85523
4@115D4@140D5@95D 9@100D
C85523-73
61+-4@10D5@90B 9@60B 17@55D
Chr15@81
11.911.2
Cbx6
72+-4@10D4@60D 5@95B 9@45B
Ntsr2
73 73neurotensinreceptor 2
77+-9@60B12@100D19@50DX@60
AW124133
73+++
9@65D12@65B17@55B
C76439
65+-2@5B 9@459@65X@10D
Ramp2
69
-69
69
Crip2
79
73
75
-77
81chromobox homolog6
72
71
hippocampus 38.5kDa
83 72+-4@10D4@45D 19@45D X@80D
Slc9a3r1
sodium/hydrogen exchangerisoform3regulator 1
86
XX+-4@XXD5@90B 9@60B 17@55D
Chr4@138
1X.911.2
Casp9
caspase9AI115399
86++++
9@65D12@[email protected]
Tceb1
transcription elongationfactor B 1
84
76 63+-1@95B 5@50B12@45B
Casp3
caspase3, apoptosisrelatedcysteineprotease
-69
-72
xx
79
dopamine receptor D2
receptor activitymodifyingprotein 2cysteinerich protein 2
4@60D6@100D 13@95D X@15D
Scamp3Chr3 @9010.48.7
secretorycarrier membraneprotein 3
4@60D6@100D 13@95D X@15D
Scamp3Chr3 @9010.48.7
secretorycarrier membraneprotein 3
Ethanol-induced conditioned place preference
742@5B4@100B7@95B 8@7518@15D
Chr13 @ 85 Mb
Chr2 @ 5 Mb
Chr9 @ 65 Mb
68+-1@175D4@65B
Chr12@39
Dnaj homologsubfamiyB9
11.010.1
Dnajb9
68+-1@175D4@65B
Chr12@39
Dnaj homologsubfamiyB9
11.010.1
Dnajb9
56+-74+++
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
AcknowledgementsUniversity 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)