The aggregate effect of dopamine genes on dependence symptoms among cocaine users: cross-validation of a candidate system scoring approach.

paper Primary Public

Authors: Derringer, Jaime; Krueger, Robert F; Dick, Danielle M; Aliev, Fazil; Grucza, Richard A; Saccone, Scott; Agrawal, Arpana; Edenberg, Howard J; Goate, Alison M; Hesselbrock, Victor M; Kramer, John R; Lin, Peng; Neuman, Rosalind J; Nurnberger, John I; Rice, John P; Tischfield, Jay A; GENEVA consortium; Bierut, Laura J
Year: 2012
Journal: Behavior genetics
PMID: 22358648
DOI: 10.1007/s10519-012-9531-4
PMCID: PMC3416038

#	Section	Preview
0	Dopamine and cocaine	Substantial evidence implicates dopamine as the primary neurotransmitter system involved in the…
1	Dopamine and cocaine	Candidate gene studies further support the association between dopamine and response to cocaine, by…
2	Dopamine and cocaine	Substantial candidate gene research has also examined the dopamine receptor D1 gene (DRD1) for…
3	Dopamine and cocaine	While individual differences in the dopamine system are not sufficient to solely account for…
4	The genetic scoring method	Given the wide range in severity of observed phenotypes in substance use and dependence, it is…
5	The genetic scoring method	One method for reducing the inclusion of the noise variants would be to increase the size of the…
6	The current study	Similar to prior scoring endeavors (e.g., International Schizophrenia Consortium, 2009; Evans et…
7	The current study	The current study sought to identify SNP variation that was associated with individual differences…
8	The current study	cocaine dependence symptoms were first identified in an initial discovery sample. The replication of…
9	Methods — Participants	In order to examine the genetic contribution to problems among cocaine users, only individuals who…
10	Methods — Participants	The present sample included 1591 unrelated individuals from the Study of Addiction: Genetics and…
11	Methods — Measure	The current study utilized DSM-IV-TR cocaine, alcohol, nicotine, and marijuana dependence symptom…
12	Methods — Genotyping	DNA was obtained from blood or lymphoblastoid cell lines, and genotyping was carried out on the…
13	Methods — Genotyping	A literature search was used to identify relevant autosomal dopamine-related genes. Genes were…
14	Methods — Statistical Analyses	The current analysis is similar to that described by the International Schizophrenia Consortium…
15	Methods — Statistical Analyses	Our sample was split randomly into training and testing samples of equal size. Although the…
16	Methods — Statistical Analyses	Initially, the standardized residuals of cocaine dependence symptom counts were regressed separately…
17	Methods — Statistical Analyses	Following the individual SNP association tests within the testing sample, ”risk scores” for each…
18	Methods — Statistical Analyses	Risk scores were therefore linear combinations of the included SNPs, weighted by their…
19	Results	Results from the top-ranked SNPs (by p-value) associated with cocaine dependence symptoms in the…

Name	Type
48bp VNTR in DRD4 local	variant
African	cohort
African American	cohort
age	phenotype
aggregate SNPs local	variant
alcohol	phenotype
alcohol dependence	phenotype
Alcohol Dependence Symptoms	phenotype
ANKK1	gene
behavioral response local	phenotype
borderline personality traits local	phenotype
brain glucose metabolism	phenotype
candidate SNP	cohort
cocaine	phenotype
Cocaine-based genetic risk score local	variant
Cocaine dependence symptom count local	phenotype
Cocaine-derived genetic risk score local	drug
Cocaine-derived SNP score local	variant
cocaine genetic risk score local	drug
Cocaine response local	phenotype
cocaine self-administration	phenotype
cocaine use disorder	phenotype
Cocaine Users Cohort local	cohort
COGEND	cohort
Collaborative Study on the Genetics of Alcoholism (COGA)	cohort
complex traits	phenotype
COMT	gene
conditioned place preference	phenotype
current sample	cohort
D1-like agonist local	drug
D2-like agonist local	drug
DBH	gene
DDC	gene
dependence symptom count local	phenotype
Detroit	cohort
diagnostic dichotomization local	phenotype
discovery sample	cohort
dopamine	drug
dopamine-related genes	gene
dopaminergic genes local	gene
Dopaminergic system	drug
Dopamine transporter	drug
DRD1	gene
DRD2	gene
DRD3	gene
DRD4	gene
DRD5	gene
drug-seeking behavior	phenotype
European ancestry	cohort
Family study of cocaine dependence	cohort
Four SNPs local	variant
four-SNP score local	variant
frequency or quantity of use local	phenotype
FSCD	cohort
genetic variants	cohort
heavy drinking	phenotype
Hispanic	phenotype
independent testing sample local	cohort
Independent testing sample local	cohort
informant- and self-report measures local	phenotype
initial training sample local	cohort
International schizophrenia Consortium	cohort
Liability to cocaine addiction local	phenotype
locomotion	phenotype
marijuana	phenotype
marijuana dependence	phenotype
marijuana dependence severity local	phenotype
Marijuana dependence symptom count local	phenotype
nicotine	drug
nicotine dependence	phenotype
Nicotine dependence symptom count local	phenotype
nicotine withdrawal	phenotype
non-Hispanic ancestry local	phenotype
nucleus accumbens	anatomy
original training sample local	cohort
PC1	phenotype
PC2	phenotype
prefrontal cortex	anatomy
problem use severity local	phenotype
propensity to use local	phenotype
R local	drug
replication testing sample local	cohort
risk score local	phenotype
rs1079597 local	variant
rs1611131 local	variant
rs1800497	variant
rs5326 local	variant
rs9817063 local	variant
SAGE	cohort
Saint Louis local	cohort
schizophrenia	phenotype
sex	phenotype
SLC6A3	gene
SLC6A3 knockout mice local	cohort
SNP	cohort
Spain	cohort
Study of Addiction: Genetics and Environment	cohort
Study source local	cohort
substance dependence symptom counts local	phenotype
substance-general genetic risk score local	phenotype
substance use	phenotype
substance use phenotypes	phenotype
tardive dyskinesia	phenotype
testing sample local	cohort
Testing sample local	cohort
tobacco dependence	phenotype
tobacco dependence severity local	phenotype
tobacco use	phenotype
Tourette syndrome	phenotype
training set	cohort

Citation	PMID	DOI	Status
Achenbach, TM et al., Psychological Bulletin, 2005, Assessment of adult psychopathology: Meta-analyses and implications of cross-informant correlations	15869333	10.1037/0033-2909.131.3.361	Cited
Amin, N et al., Eur J Epidemiol, 2009, Genetic scoring analysis: A way forward in genome wide association studies?	19728114	10.1007/s10654-009-9387-y	Cited
Begleiter, H et al., Alcohol Health Res World, 1995, The Collaborative Study on the Genetics of Alcoholism	31798102	—	Primary
Beuming, T et al., Nat Neurosci, 2008, The binding sites for cocaine and dopamine in the dopamine transporter overlap	18568020	10.1038/nn.2146	Cited
Bierut, LJ et al., Drug Alcohol Depend, 2008, Drug use and dependence in cocaine dependent subjects, community-based individuals, and their siblings	18243582	10.1016/j.drugalcdep.2007.11.023	Primary
Bierut, LJ et al., Proc Natl Acad Sci U S A, 2010, A genome wide association study of alcohol dependence	20202923	10.1073/pnas.0911109107	Primary
Bierut, LJ, Pharmacogenomics, 2007, Genetic variation that contributes to nicotine dependence	17716221	10.2217/14622416.8.8.881	Cited
Bloch, PJ et al., Psychiatr Genet, 2009, Association analysis between polymorphisms in the dopamine D3 receptor (DRD3) gene and cocaine dependence	19503018	10.1097/YPG.0b013e32832cec12	Cited
Blum, K et al., J Psychoactive Drugs, 2000, Reward deficiency syndrome: A biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors	11280926	10.1080/02791072.2000.10736099	Cited
Briand, LA et al., Neuropsychopharmacology, 2008, Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine	18305460	10.1038/npp.2008.18	Cited
Bucholz, KK et al., J Stud Alcohol, 1994, A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA	8189735	10.15288/jsa.1994.55.149	Primary
Buckland, PR, Addiction, 2008, Will we ever find the genes for addiction?	18705689	10.1111/j.1360-0443.2008.02285.x	Cited
Caine, SB et al., J Neurosci, 2007, Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice	18045908	10.1523/JNEUROSCI.2284-07.2007	Cited
Chen, K et al., Drug and Alcohol Dependence, 2002, Relationship between extent of cocaine use and dependence among adolescents and adults in the United States	12167553	10.1016/s0376-8716(02)00086-8	Cited
Dackis, CA et al., Neurosci Biobehav Rev, 1985, New concepts in cocaine addiction: the dopamine depletion hypothesis	2999657	10.1016/0149-7634(85)90022-3	Cited
Derauf, C et al., Semin Cell Dev Biol, 2009, Neuroimaging of children following prenatal drug exposure	19560049	10.1016/j.semcdb.2009.03.001	Cited
Derringer, J et al., Psychol Sci, 2010, Predicting sensation seeking from dopamine genes: A candidate system approach	20732903	10.1177/0956797610380699	Primary
Evans, DM et al., Hum Mol Genet, 2009, Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk	19553258	10.1093/hmg/ddp295	Cited
Fernàndez-Castillo, N et al., Psychiatr Genet, 2010, Association study between the DAT1, DBH and DRD2 genes and cocaine dependence in a Spanish sample	20505554	10.1097/YPG.0b013e32833b6320	Cited
Ford, JD et al., Drug Alcohol Depend, 2009, Association of psychiatric and substance use disorder comorbidity with cocaine dependence severity and treatment utilization in cocaine-dependent individuals	18775607	10.1016/j.drugalcdep.2008.07.004	Cited
Ge, D et al., WGAViewer: Package of Whole Genome Association Annotation, 2007	—	—	—
Gillespie, N et al., Addiction, 2007, Factor and item-response analysis DSM-IV criteria for abuse of and dependence on cannabis, cocaine, hallucinogens, sedatives, stimulants and opioids	17523987	10.1111/j.1360-0443.2007.01804.x	Cited
Giros, B et al., Nature, 1996, Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter	8628395	10.1038/379606a0	Cited
Goldman, D et al., Nat Rev Genet, 2005, The genetics of addictions: Uncovering the genes	15995696	10.1038/nrg1635	Cited
Gray, JD, Can Fam Physician, 1993, Medical consequences of cocaine	8106032	—	Cited
Haile, CN et al., Behav Genet, 2007, Genetics of dopamine and its contribution to cocaine addiction	17063402	10.1007/s10519-006-9115-2	Cited
Harford, TC et al., Alcohol Clin Exp Res, 2009, The dimensionality of DSM-IV alcohol used disorders among adolescent and adult drinkers and symptom patterns by age, gender, and race/ethnicity	19320629	10.1111/j.1530-0277.2009.00910.x	Cited
Henry, DJ et al., J Pharmacol Exp Ther, 1991, Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens	1890623	—	Cited
Herzberg, I et al., Psychiatr Genet, 2010, Association of DRD2 variants and Gilles de la Tourette syndrome in a family-based sample from a South American population isolate	20431429	10.1097/YPG.0b013e32833a215a	Cited
Hesselbrock, M et al., Addiction, 1999, A validity study of the SSAGA--a comparison with the SCAN	10615721	10.1046/j.1360-0443.1999.94913618.x	Primary
Hill, WG et al., PloS Genet, 2008, Data and theory point to mainly additive genetic variance for complex traits	18454194	10.1371/journal.pgen.1000008	Cited
Hnasko, TS et al., J Neurosci, 2007, Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin	18003826	10.1523/JNEUROSCI.3133-07.2007	Cited
International Schizophrenia Consortium et al., Nature, 2009, Common polygenic variation contributes to risk of schizophrenia and bipolar disorder	19571811	10.1038/nature08185	Cited
Johnson, AD et al., Bioinformatics, 2008, SNAP: A web-based tool for identification and annotation of proxy SNPs using HapMap	18974171	10.1093/bioinformatics/btn564	Cited
Kendler, KS et al., Arch Gen Psychiatry, 2000, Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins	10711912	10.1001/archpsyc.57.3.261	Cited
Kendler, KS et al., Br J Psychiatry, 1998, Cocaine use, abuse and dependence in a population-based sample of female twins	9926041	10.1192/bjp.173.4.345	Cited
Kuhar, MJ et al., Trends Neurosci, 1991, The dopamine hypothesis of the reinforcing properties of cocaine	1719677	10.1016/0166-2236(91)90141-g	Cited
Lai, IC et al., Eur J Clin Pharmacol, 2011, Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotic-induced tardive dyskinesia in schizophrenia	21181138	10.1007/s00228-010-0967-2	Cited
Laurie, CC et al., Genet Epidemiol, 2010, Quality control and quality assurance in genotypic data for genome-wide association studies	20718045	10.1002/gepi.20516	Primary
Levran, O et al., Genes Brain Behav, 2009, Heroin addiction in African Americans: A hypothesis-driven association study	19500151	10.1111/j.1601-183X.2009.00501.x	Cited
Liu, QS et al., Nature, 2005, Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons	16222299	10.1038/nature04050	Cited
Munafò, MR et al., Biol Psychiatry, 2008, Association of the Dopamine D4 Receptor (DRD4) gene and approach-related personality traits: Meta-analysis and new data	17574217	10.1016/j.biopsych.2007.04.006	Cited
Munafò, MR et al., Molecular Psychiatry, 2007, Association of the DRD2 gene Taq1A polymorphism and alcoholism: A meta-analysis of case-control studies and evidence of publication bias	17453061	10.1038/sj.mp.4001938	Cited
Munafò, MR et al., Nicotine & Tobacco Research, 2009, Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data	19246443	10.1093/ntr/ntn012	Cited
Nemoda, Z et al., Behav Brain Funct, 2010, Association between dopaminergic polymorphisms and borderline personality traits among at-risk adults and psychiatric inpatients	20205808	10.1186/1744-9081-6-4	Cited
Nichol, PE et al., Alcohol Clin Exp Res, 2007, Investigating gender differences in alcohol problems: a latent trait modeling approach	17386067	10.1111/j.1530-0277.2007.00375.x	Cited
Nutt, D et al., Lancet, 2007, Development of a rational scale to assess the harm of drugs of potential misuse	17382831	10.1016/S0140-6736(07)60464-4	Cited
Plomin, R et al., Nat Rev Genet, 2009, Common disorders are quantitative traits	19859063	10.1038/nrg2670	Cited
Price, AL et al., Nat Genet, 2006, Principal components analysis corrects for stratification in genome-wide association studies	16862161	10.1038/ng1847	Cited
R Development Core Team, R: A language and environment for statistical computing, 2009	—	—	—
Robinson, JD et al., Pharmacogenomics J, 2007	17189962	10.1038/sj.tpj.6500427	Cited
Rocha, BA et al., Nat Neurosci, 1998, Cocaine self-administration in dopamine-transporter knockout mice	10195128	10.1038/381	Cited
Self, DW et al., Science, 1996, Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists	8599115	10.1126/science.271.5255.1586	Cited
Shaffer, HJ et al., Addiction, 2002, Temporal progression of cocaine dependence symptoms in the US National Comorbidity Survey	12033655	10.1046/j.1360-0443.2002.00114.x	Cited
Sora, I et al., Proc Natl Acad Sci USA, 1998, Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice	9636213	10.1073/pnas.95.13.7699	Cited
Substance abuse and mental health services administration (SAMHSA), Results from the 2008 National Survey on Drug Use and Health: National Findings, 2009	—	—	—
Thanos, PK et al., Synapse, 2008, The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice	18286542	10.1002/syn.20503	Cited
Ungless, MA et al., Nature, 2001, Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons	11385572	10.1038/35079077	Cited
van den Bree, MB et al., Drug and Alcohol Dependence, 1998, Genetic and environmental influences on drug use and abuse/dependence in male and female twins	9839149	10.1016/s0376-8716(98)00101-x	Cited
Volkow, ND et al., Nature, 1997, Relationship between subjective effects of cocaine and dopamine transporter occupancy	9126740	10.1038/386827a0	Cited
Vukcevic, D et al., Genet Epidemiol, 2011, Disease model distortion in association studies	21416505	10.1002/gepi.20576	Cited
Xu, M et al., Cell, 1994, Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice	8001143	10.1016/0092-8674(94)90026-4	Cited
Zuk, O et al., Proc Natl Acad Sci U S A, 2012, The mystery of missing heritability: Genetic interactions create phantom heritability	22223662	10.1073/pnas.1119675109	Cited

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