Functional alleles & intermediate phenotypes in alcoholism ... · Functional alleles & intermediate...
Transcript of Functional alleles & intermediate phenotypes in alcoholism ... · Functional alleles & intermediate...
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Functional alleles & intermediate phenotypes in alcoholism and
dyscontrol disorders
David [email protected]
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1935-2006
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Begleiter, H., and Platz, A. (1969). Evoked potentials: Modifications by conditioning. Science 166:769-771.
Begleiter, H., Porjesz, B., Yerre, C., and Kissin, B. (1973). Evoked potential correlates of expected stimulus intensity. Science 179(4075):814-816.
Begleiter, H., and Porjesz, B. (1975). Evoked brain potentials as indicators of decision-making. Science 187:754-755.
Begleiter, H., and Porjesz, B. (1975). On evoked potentials, cognition, and memory. Science 190:1004-1006.
Begleiter, H., Porjesz, B., and Chou, C.L. (1981). Auditory brainstem potentials in chronic alcoholics. Science 211:1064-1066.
Begleiter, H., Porjesz, B., Bihari, B., and Kissin, B. (1984). Event-related potentials in boys at risk for alcoholism. Science 225:1493-1496.
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The heritability of addictive disorders
h2
+
range
0
0.2
0.4
0.6
0.8
1
High
low
Mean
Halluc
inoge
ns (45
70)
Stimula
nts (2
212)
Canna
bis (7
659)
Sedati
ves (
4758
)Gam
bling
(335
9)Smok
ing (1
0620
)Alco
hol (9
897)
Caffein
e (69
97)
Cocain
e (22
06)
Opiates
(349
4)
Nature Genetics Reviews, 2005
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Frontal cortical function/behavioral inhibitionDrug metabolism and response/toleranceRewardAnxiety-dysphoria/stress responseObsession/Craving
ElectrophysiologyImaging: brain structure and functionNeuropsychologyMetabolomicsGene expression
Alcoholism and other addictions: The intermediate phenotypes
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Gene, stress, & substances in dyscontrol
MAOA rare & common alleles: GxE, fMRICOMT Val158Met: Roles in cognition & resiliency
HTTLPR: GxE for depression and suicidality
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Genes with alleles proven to modulate human behavior
MAOA Brunner SyndromeHTT
OCD
HPRT Lesch-Nyhan SyndromeERBA ADHDMAOA* DyscontrolHTT* Anxiety, OCDCOMT Cognition, anxietyBDNF Episodic memoryALDH2 AlcoholismADH1B Alcoholism
Rare
Probablistic
Deterministic
Common
*Regulatory
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Odds ratio
21 3 4
Disease
Intermediate phenotype
CADCrohn
For risk genes, odds ratios
are larger for Intermediate Phenotypes than for
Diseases (Wellcome Trust medians)
BP
RA
T1DT2D
Median of 24 disease loci
5 6
WCST/COMT
HTTLPR/Amygdala fMRI
HTTLPR/HA MAOA/
Amygdala fMRI
MAOA/Orbitofrontal fMRI
MAOA/Hippo fMRI
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Brunner et al.,
Science, 1993
Brunner syndrome: X-linked dyscontrol due to the MAOA C936T
stop-codon
Borderline mental retardation
Dyscontrol behaviors:Aggressive outburstsArsonAttempted rape Exhibitionism
.
.
..
.
.
C
CCCCC
C
C C
CC CC
C
C
C
TTT T
T
T
T
No fibroblast MAOA activity
Abnormal monoamine metabolism: ↓
urinary HIAA, HVA, VMA↑
urinary normetanephrine & tyramine
T
Unaffected
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Expanding the stress connection to behavioral dyscontrol:
Predisposition, early exposure, and substance abuse
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Child sexual abuse and psychiatric disorders in females
•
ASPD 2.9
[1.4-6.0]•
Alcoholism [Abuse +Dep]
2.1
[1.2-3.6]
•
Substance abuse
4.2
[2.2-7.8]•
Affective disorder
2.3
[1.3-4.0]
•
Anxiety disorder
1.8
[1.0-3.1]•
PTSD
5.3
[2.2-12.7]
Robin et al, Amer J. Psychiatry, 1997
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Addictions: A cause and effect of stress/trauma and dyscontrol
•
Key factor in accidents, violence and sexual trauma
•
A consequence of trauma•
Consequences of underage drinking
•
A cause of allostatic changes•
Genes mediate liability
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0
5
10
15
20
25
*HA(±SE)
Finns(433)
COGA (511)
Plains Indian(350)
Bethesda(148)
ControlsAD,
ASPD -
AD,
ASPD +
Alcoholics Tend to Be Anxious
* *
*
Ducci et al, 2007
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G. Koob, B. McEwen
Allostasis and Addiction
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Sabol et al, Hum Genet, 1998
vector 3 3.5 4 5
vector 3 3.5 4 5 vector 3 3.5 4 5
A functional promoter polymorphism (MAOA-LPR) predicts MAOA expression
Repeats33.545ACCGGCACCGGCACCAGTACCCGCACCAGT
MAOA promoterMAOA
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Caspi et al. Science., 2002
GxE interaction of MAOA-LPR and childhood maltreatment on antisocial behavior, in males
Com
posi
te in
dex
of
antis
ocia
l beh
avio
r (z
scor
es)
Childhood maltreatment
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Childhood Sexual AbuseNoYes
3/3 4/4 3/3 3/4 4/4
Popu
latio
n fr
actio
n
0.00
0.20
0.40
0.60
0.80
1.00
ASPD + AUD
AUD, no ASPD
Unaffected
Ducci et al, Molecular Psychiatry, 2007
3/4
GxE interaction of MAOA-LPR & childhood sexual abuse for
ASPD & alcoholism
Repeats33.545ACCGGCACCGGCACCAGTACCCGCACCAGT
MAOA promoterMAOA
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0
5
10
15
20
25
30
35
100 200 300 400 500 600
Testosterone (pg/mL)
βa
(SE) = 3.49 (1.01); p=0.001
Bro
wn/
Goo
dwin
Li
fetim
e A
ggre
ssio
n
ASPD + AUDAUD, no ASPDno AUD, no ASPD
βa
(SE) = −0.94 (1.04); p=0.37
High activity MAOA-LPR
0
5
10
15
20
25
30
35
100 200 300 400 500 600
Non-additive interaction of MAOA-LPR and testosterone predicts antisocial behavior
Sjoberg et al., Neuropsychopharmacology 2007
Low activity MAOA-LPR
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Andreas Meyer-Lindenberg (2006) PNAS 103, 6269-6274
MAOA-LPR predicts differential fMRI activations to angry and fearful faces in limbic and paralimbic regions (n = 142)
L AmygdalaOrbitofrontalCortex
SubgenualCingulate
SupragenualCingulate
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MAOA-LPR predicts fMRI limbic activations during retrieval of aversive memories (n = 90)
Andreas Meyer-Lindenberg (2006) PNAS 103, 6269-6274
L Amygdala
L Hippocampus
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rhMAOA-LPR
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COMT Val158Met: Apparent counterbalancing effects in
cognition
and stress/anxiety
Warrior
Worrior
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WC
STPe
rsev
erat
ive
Err
ors (
t-sc
ores
)
30
35
40
45
50
55
60
Val/Val Val/Met Met/Met
Siblings
Patients
Controls
N = 449F = 6.00p = .003
COMT Val158Met and WCST
55
219
175
Egan et al, PNAS, 2001
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Fear of Uncertainty (HA2) and
COMT Val158Met in females from two populations
Enoch et al, Psychiatric Genetics, 2003
(HA2)
Val/Val Val/Met Met/Met
4
5
6
Plains Indian[N = 148, F=3.5, p=0.03, 2 df]
U.S. Caucasian[N = 75, F=3.5, p=0.09, 2 df]
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[11C]-Carfentanil binding in brain
amygdala
globus pallidus,n. accumbens
thalamus
cingulate
Source:Jon-Kar Zubieta
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COMT Met158Val and µ-opioid system activation in response to sustained pain
Zubieta et al, Science, 2003
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HTT1200 nt
S allele
L allele HTT
14 repeats
16 repeats
CCCCCCTGCACCCCCCGGCATAP2
A>G
Hu et al, AJHG, 2006
HTTLPR: Still psychiatric genetics’most popular locus
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GxE: Interaction of HTTLPR and stress in depression
Caspi et al, Science 2003
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Gene x Environment (HTT x Childhood stress) predicts suicide attempts in abstinent,
African American, Substance Dependent patients (N=306)
CTQ Emotional Neglect CTQ Physical Abuse
Prob
abili
ty o
f Sui
cide
A
ttem
pt
Roy et al, In press
10 20 30 40 50
CTQ Emotional Neglect
0.20
0.40
0.60
0.80
1.00
Pred
icte
d pr
obab
ility
of a
sui
cide
atte
mpt
HTTLPR genotypehigh explow exp
0 5 10 15 20 25 30
CTQ Physical Abuse
0.20
0.40
0.60
0.80
1.00
Pred
icte
d pr
obab
ility
of a
sui
cide
atte
mpt
HTTLPR genotypehigh explow exp
HTT genotypesLow expressingHigh expressing
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Anxiety,Resiliency
Functional Allele to Complex Behavior
Alcoholism
EnvironmentalFactors
OCD
Marker phenotype
HTTHTTLPR
COMTVal158Met
Executive Cognition
BDNFVal66Met
EpisodicMemory
Schizophrenia
Trauma
MAOAGCH1 GABRA2
Pain
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Thanks!
Mary-Anne EnochZhifeng ZhouKe XuXianzhang HuFrancesca DucciRobert LipskyPeihong ShenQiaoping YuanColin Hodgkinson
Rob RobinBernard AlbaughAlec Roy
Ahmad HaririDeborah MashRajita SinhaJon-Kar Zubieta Mary HeitzigDavid Scott
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Polygenicity:
Multiple genetic variants confer risk in combination.
Heterogeneity:
Multiple genetic variants confer risk in different individuals.
Genetic Complexity
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Genetic complexity in affected populations
Polygenicity Heterogeneity
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Genetic complexity and twin concordance
Polygenicity Heterogeneity
DZ
MZ MZ
DZ
Affected Unaffected
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2.19
2.23 2.38
2.69 2.71
3.72
1.52
1.73
1.96
1.84
0 0.5 1 1.5 2 2.5 3 3.5 4
MZ/DZ
Lack of evidence for polygenic inheritance of addictions
CocaineSedativesStimulantsCaffeineHallucinogensOpiatesGamblingSmoking
CannabisAlcohol
2
Nature Genetics Reviews, 2005
Concordance Ratios
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Pain/Stress Challenge: Hypertonic saline infusion to masseter muscle
NaCl infusion rate
Pain
Muscle
NaCl
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COMT yin/yang haplotypes in five populations &
Linkage to Opioid addiction & Alcoholism
ChineseAfrican American
German CaucasianFinnish Caucasian
Plains Indian
0.25 0.240.09 0.080.24 0.280.15 0.270.09 0.22
MV
.02
.03.003
Case/Control477/361167/294490/192
p value
178/283175/175
<.001
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COMT Val158Met and Addiction
•
Polysubstance abuse: Val158 –
Vandenburgh, Uhl and colleagues
•
Late onset alcoholism: Met158–
[Hallikainen et al, 2000] 62 early onset, 132 late onset, 267 controls. Odds ratio of 3 for late onset, p=0.017
–
[Tiihonen et al, 1999] 67 & 56 late onset, 3140 blood donors, 267 matched controls. Met/Met vs Val/Val Odds ratio 2.5, p =0.006, Attributable risk for Met/Met vs Val/Val 13.3%
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COMT Val158Met
Val158 Met158
High anxiety,Stress reactive
Alcoholism and other substance abuses
BehavioralDyscontrol
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Val158/Met158Val/Val Val/Met Met/Met G/G C/G C/C
rs4818
Mea
n z-
scor
e (±
se)
-6-4-20246
G/G A/G A/A
rs6269ANOVA: p=0.18 p<0.01 p<0.01
Replication of COMT in experimental pain in 202 females prospectively followed for TMJ
(Diatchenko et al, Hum Mol Genetics, 2005)
-6-4-20246
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Chromosome 4
0.00001
0.0001
0.001
0.01
0.1
10 20 40 60 80 100 120 140 160 180 200 220
cM from pter
p-va
lue
Multi-point2-point
GABAA
Cluster
ADH Cluster
Long et al, 1998
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GABRA2 LD and Alcoholism Linkages
Kranzler et alEdenberg et al
Enoch et al
***
**
**
**
Same alleles,Same haplotype
HaplotypeTagging
112112122122122212211
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Addictions Array for 130 Candidate Genes
•
1536 SNPs •
Tagging of haplotypes > 0.6% in frequency
•
Avg of >11 SNPs/gene, Range 4 -
35•
186 “perfect”
genomic control SNPs (AIMs)
–
Balanced set with cross-population Δ>0.7, and >10x•
$ <0.05/genotype
•
25,000 individuals genotyped (Yale, Rockefeller, Wash U, Columbia [2], Univ. Colorado, Emory, VCU, NICHD)
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ALDH1AALDH2CATCYP2E1 ADH1AADH1BADH1CADH4ADH5ADH6ADH7
Metabolic
DDCDRD1DRD2DRD3DRD4DRD5SLC18A2THCOMT
Dopamine
SerotoninHTR1AHTR1BHTR2AHTR2CHTR3AHTR3BMAOAMAOBSLC6A3SLC6A4TPH2
GABA
CNR1FAAH
CHRM1CHRM2CHRM3CHRM4CHRM5CHRNA4CHRNB2
CRHCRHBPCRHR1CRHR2GALNPYNPY1RNPY2RNPY5R
ADCY7AVPR1AAVPR1BCDK5R1CREB1CSNK1EFEVFOSFOSL1FOSL2GSK3BJUNMAPK1MAPK3MPDZNGFBNTRK2NTSR1NTSR2PPP1R1BPRKCE
BDNFCCKCCKARCCKBRCLOCKHCRTOXTNR3C1SLC29A1TAC1CART
GABRA2GABRA4GABRA6GABRB1GABRB2GABRB3GABRDGABRG2GABRG3SLC6A11SLCSA13GAD1GAD2VIAATDBI
OPRM1OPRD1OPRK1OPRL1PDYNPENKPNOCPOMC
GLRA1GLRA2GLRBGPHN
GRIK1GRIN1GRIN2AGRIN2BGRM1
ADRA1AADRA2AADRA2BADRA2CADRB2ARRB2SLC6A2DBH
Opioid
GlycineNMDACannabinoid
Signal Transduction
AdrenergicHPA & Stress
Cholinergic
OtherAddictions Array
130 GenesTagged with 1350 SNPs
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Finns Plains Indians Han Chinese African American
0.980.010.010.00
0.050.920.020.00
0.010.010.980.00
0.110.020.020.85
Assignment of ancestry with 186 Ancestry-informative SNPs(Structure2, Four-factor solution)
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Ethnic factor scores of 1051 individuals in 52 CEPH populationwith 186 AIMs
7-factor solution, Structure 2
Africa MiddleEast
Asia Oceania Europe America
Hodgkinson et al, unpublished
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Human
Mac
aque
Repeats in the 5 Kb region upstream of 5-HTT in Macaca mulatta and Homo sapiens
20-22 bpImperfect
repeats
SequenceIdentity
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Peer-reared
Mother-reared
Alco
hol p
refe
renc
e
ls lsll ll
Biol Psych 55: 733, 2004
Arch Gen Psych 61: 1146, 2004
rh-HTTLPR has GxE effects on alcohol
preference & stress response
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Serotonin Transporter Genetic Variation and the Response of the Human Amygdala
Science 2002 July 19; 297(5580):400-3
Ahmad R. Hariri,1
Venkata S. Mattay,1
Alessandro Tessitore,1
Bhaskar Kolachana,1
Francesco Fera,1
David Goldman,2Michael F. Egan,1
Daniel R. Weinberger1*
1
Clinical Brain Disorders Branch, NIMH, NIH.2
Laboratory of Neurogenetics, NIAAA, NIH.
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Nature Neuroscience 8, 828 - 834 (2005) 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions:
a genetic susceptibility mechanism for depressionLukas Pezawas, Andreas Meyer-Lindenberg, Emily M Drabant, Beth A Verchinski, Karen E Munoz, Bhaskar S Kolachana, Michael F Egan, Venkata S Mattay, Ahmad R Hariri & Daniel R Weinberger
Statistical functional connectivity maps between bilateral amygdala and perigenual anterior cingulate cortex
LL Sx
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A common, functional NPY haplotype influencing anxiety and stress response (Zhifeng Zhou et al, submitted)
•
The common haplotype predicts reduced brain and lymphoblast mRNA levels and plasma NPY
•
The reduction of function haplotype predicts:–
Trait anxiety
–
Reduced amygdala emotional fMRI activation–
Reduced amygdala pain/stress induced opioid release
•
A functional promoter locus was identified via in vitro reporter constructs
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A functional human GCH1 haplotype predicts post-diskectomy clinical pain and experimental pain
547 normalcontrols
162 post-diskectomy
patients
Tegeder et al, Nature Medicine, 2006
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Pain-enhanced GCH1 expression in the Dorsal Root Ganglion
Tegeder et al, Nature Medicine, 2006
GCH1 mRNA and protein in rat DRGare upregulated by nerve injury
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Tegeder et al, Nature Medicine, 2006
Biopterin synthesis in rat DRGis upregulated by nerve injury and blocked
by a GCH1 inhibitor
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Rapid inhibition of pain and DRG neuronal activation by the GTP cyclohydrolase inhibitor,
2,4-diamino-6-hydroxypyrimidine (DAHP)
Tegeder et al, Nature Medicine, 2006
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Genotype-predicted NPY expression predicts pain/stress induced opioid activation
Zhou et al, submitted
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T Value
Amygdala
Hippocampus
0
0.5
1
1.5
2
2.5AmygdalaHippocampus
NPY Diplotype
LL LH
Act
ivat
ion
(Arb
itrar
y U
nits
)
(n = 11) (n = 42)
P = 0.003
LL HH
fMR
I
(n = 18)
P = 0.003
P = 0.006
Genotype-predicted NPY expression predicts emotion-induced fMRI activation
Zhou et al, submitted
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1.5
2
2.5
3
3.5
4
0.5 1.0 1.5 2.0 2.5 3.0 3.5
NPY mRNA Expression Level
HA
1 an
d H
A2
Subs
core
s
HA1HA2
R 2 = 0.0338P = 0.0314
R 2 = 0.0326P = 0.0346
Genotype-predicted NPY expression predicts anxietyZhou et al, submitted
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Anxiety,Resiliency
Functional Allele to Complex Behavior
Alcoholism
EnvironmentalFactors
OCD
Marker phenotype
HTTHTTLPR
COMTVal158Met
Executive Cognition
BDNFVal66Met
EpisodicMemory
Schizophrenia
Trauma
NPYGCH1 GABRA2
Pain
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HTTLPR and anxiety [Sen, Burmeister and Ghosh, 2004]
•
26 Studies, 5,629 subjects•
p = 0.087
•
Substantial effect of inventory and inter-study heterogeneity
•
p < 0.000016, NEO, corrected for heterogeneity•
0.1 SD increment in TPQ Harm avoidance or NEO Neuroticism per ”s”
allele
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Triallelic Functionality at HTTLPR
•
S and LG
are equivalent in expression in lymphoblasts and raphe-derived neurons
•
AP2 transcription factor binds to LG and acts as a repressor of transcription–
Gel-shift and supershift assays
–
Allele-specific, AP2-specific decoy DNA eliminates the LA
:LG
difference
Hu et al, AJHG, 2006
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Ile425Val
HTT
Ozaki et al, Mol Psych, 2003
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Replication of HTTLPR-OCD linkage inParent/child trios
Collaboration with James Kennedy, Clarke Centre, Toronto
Triallelic
Transmitted
Untransmitted
S LALG
1127 48
1644 26
p = 0.023
Low/High
S, LG LA
20
20
41
41
p = 0.010
Hu et al, AJHG, 2006
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SS SLA
SLG LA
LA
LA
LG
LG
LG
S LA
LGOCD
0.21 0.34 0.03 0.34 0.07 0.01 0.38 0.56 0.06Control 0.16 0.47 0.08 0.19 0.08 0.02 0.44 0.47 0.10
χ 2
= 19.4 χ 2
= 6.6p = 0.001 p = 0.036
SS SL LL
S LOCD 0.21
0.37 0.42
0.39
0.61Control 0.16 0.55
0.29 0.44
0.56
χ 2
= 15.0
χ2 = 1.5p = 0.001
p = 0.216
HTTLPR genotype and allele frequencies in 169 OCD patients and 253 controls
Genotypes Alleles
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0
5
10
15
20
25
30
35
100 200 300 400 500 600
Testosterone (pg/mL)
βa
(SE) = 3.49 (1.01); p=0.001
Bro
wn/
Goo
dwin
Li
fetim
e A
ggre
ssio
n
ASPD + AUDAUD, no ASPDno AUD, no ASPD
βa
(SE) = −0.94 (1.04); p=0.37
High activity MAOA-LPR
0
5
10
15
20
25
30
35
100 200 300 400 500 600
Non-additive interaction of MAOA-LPR and testosterone predicts antisocial behavior
Sjoberg et al., Neuropsychopharmacology 2007
Low activity MAOA-LPR