The imaging genetics study in heroin addiction Jie Shi National
Institute on Drug Dependence, Peking University
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Harm of drug addiction Induce fraud, violent crime,
prostitution, etc Cause a direct economic loss of more than 200
billion a year Impair individual health and cause higher death rate
Cause spread of infectious diseases such as HIV, HCV, etc China
Narcotics Control Report in 2014 Registered drug addicts (10 4 )
2
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Harm of heroin addiction Heroin addiction has been associated
with multiple impaired behavioral functions, such as global
cognition, impulsive decision- making and impulsivity Drug Alcohol
Depend, 2008 J Psychopharmacol, 2010 Repeated exposure to heroin
could result in persistent molecular and morphological changes in
the brain J Neuropsychiatry Clin Neurosci., 2007 Science, 2012
3
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Genetic factors in drug addiction Heroin addiction was
influenced by genetic factors to a greater degree than other drug
addiction. Arch Gen Psychiatry., 1998 Applying genetic approaches
would contribute great to addiction therapy methods Pharmacol
Ther., 2005 Oncogene., 2002 4 Opiate addiction Genetic factors Drug
addiction Nat Genetic., 2005
Imaging Genetics Curr Opin Genet Dev. 2011 Imaging genetics is
a form of genetic association analysis It provide a unique tool to
explore the functional impact of brain relevant genetic
polymorphisms, which may thus fill the gap between the gene and the
diagnostic category 6
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Imaging Genetics Curr Opin Genet Dev. 2011 7
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Limited to the single candidate gene association in small
sample The study of genetic effects on addiction-related phenotype
is still in its infancy The mechanism underlying the association is
unclear 8 Gene Cell Behavior Brain Current limitations of genetics
studies in addiction 8
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Imaging genetics study in heroin addiction Genetic effects on
endophenotypes Recruiting subjects and collecting genetic sample
Brain network Brain morphometry Behavior tests Animals or
multi-modal analysis and molecular biology experiments Screening
candidate genetic risk factors Verified in large sample
Endophenotype Genetic association analysis Genetic regulatory
mechanism 9
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Research contents Behavioral and imaging abnormality of heroin
addicts 1 The genetic risk factors of heroin addiction 2
Association analysis between ZNF804A variants and heroin addiction
Association analysis between MAOA variants and heroin addiction
10
Slide 11
Research contents Behavioral and imaging abnormality of heroin
addicts 1 The genetic risk factors of heroin addiction 2
Association analysis between ZNF804A variants and heroin addiction
Association analysis between MAOA variants and heroin addiction
11
Behavioral abnormalities of heroin addicts Heroin addicts
showed significantly worse cognition and impulsivity Montreal
cognitive assessment (MoCA) Barratt Impulsiveness Scale (BIS -11)
Iowa gambling task (IGT) 13
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Gray matter abnormality of heroin addicts 14 The gray matter of
heroin addicts showed widely atrophy, mainly in frontal and
temporal lobe.
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White matter abnormality of heroin addicts 15 The FA value of
white matter in heroin addicts was widely increased, mainly in
corpus callosum and inferior longitudinal fasciculus.
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Disrupted network connectivity in heroin abusers 16 The
subnetwork was significantly increased in heroin abusers, which can
be categorized into 3 systems: default-mode system, attention
system and vision system.
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Relationships between network metrics and clinical variables
and performance 17 Within-frontal connection strength was
positively associated with daily dosage of heroin use (A),
within-temporal connection strength was negatively associated with
non-planning scores on BIS-11 (B).
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Brain functional system network Impulsive/reflective
dual-system network Cognitive control system network Reward system
network 18
The Impulsive/reflective network in heroin addicts Normal vs
addiction, p 100 20 The impulsive control network was significantly
abnormal in heroin addicts. The most significant area is
insula.
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Research contents Behavioral and imaging abnormality of heroin
addicts 1 The genetic risk factors of heroin addiction 2
Association analysis between ZNF804A variants and heroin addiction
Association analysis between MAOA variants and heroin addiction
21
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Candidate SNPs 1.Validated genetic risk factors for addiction:
COMT, BDNF, HTR2A, MAOA, CNR1 2. Molecules critical for psychiatric
disorders : Orexin receptor, GSK-3, TrkB 3. MicroRNA related to
psychosis: Mir-146a, Mir-137 4. Genetic risk factor in other
psychiatric disorders: ZNF804A, CACNA1C 22
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ZNF804A rs1344706 is the first genetic variant to achieve
genome wide significance for psychosis that the A allele is
associated with increased risk for schizophrenia. Nat Genet, 2008
Rs1344706 was significantly associated with expression of ZNF804A
mRNA, and the disease risk A allele was associated with higher
expression. Mol Psychiatry, 2011 ZNF804A knockdown on the
expression of genes involved in cell adhesion, suggesting a role
for it in processes such as neural migration, neurite outgrowth and
synapse formation. Hum Mol Genet, 2012 ZNF804A may affect the
transcription of PRSS16 and COMT (up) and PDE4B and DRD2 (down),
DRD2 plays an important role in addiction. Biol Psychiatry, 2012 23
ZNF804A variants
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Large genetic sample Heroin addicts 1036 (726 male, 309 female)
Han South of China native Age 30-60 Education: 9 -12 year Controls
2887 (1313 male, 1574 female) 24
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The candidate SNPs in ZNF804A SNPs in coding exons and critical
synonymous SNPs in the intron SNP_IDGENEMAF rs1344706ZNF804A 0.453
rs7597593ZNF804A 0.402 rs12476147ZNF804A 0.221 rs4667001ZNF804A
0.189 rs1366842ZNF804A 0.179 rs12477430ZNF804A 0.163 25 The
candidate SNPs were in high linkage disequilibrium D value r2
value
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The ZNF804A variants were significant associated with heroin
addiction 26
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The variants in ZNF804A associated gene were significant
correlated with heroin addiction Proteins interacting with ZNF804A
(BioGRID) The critical SNPs associated with heroin addiction
Results SNP_IDGENEMAF rs10946904PRSS16 0.289 rs2144719PDE4B 0.151
rs879471STMN3 0.163 rs10804166C2ORF80 0.122 rs1079597DRD2 0.5
rs4680COMT 0.256 rs179943ATXN1 0.465 rs11730582SPP1 0.326
rs6265BDNF 0.4762 rs6313HTR2A 0.4359 rs1137070MAOA 0.4011
rs279871GABRA2 0.417 rs1799971OPRM1 0.36 SNP_IDGENEP value
rs10946904PRSS16p