Genome-wide association study of stimulant dependence.

paper Primary Public

Authors: Cox, Jiayi; Sherva, Richard; Wetherill, Leah; Foroud, Tatiana; Edenberg, Howard J; Kranzler, Henry R; Gelernter, Joel; Farrer, Lindsay A
Year: 2021
Journal: Translational psychiatry
PMID: 34226506
DOI: 10.1038/s41398-021-01440-5
PMCID: PMC8257618

Fig. 1

Association of stimulant dependence with SNPs located between LRP1B and KYNU in the African American discovery sample.SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs6721393. Rs6721393 was nearly genome-wide significant (P = 3.13 × 10−7) after meta-analysis with the replication sample.

Fig. 2

Association of stimulant dependence with SNPs located in the SLC25A16 region in the African American discovery sample.SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs2394476. Rs2394476 was genome-wide significant (P = 1.22 × 10−9) after meta-analysis with the replication sample.

Fig. 3

Association of stimulant dependence with SNPs located in the KCNA4 region in the African American discovery sample.SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs11500237 located 93 kb upstream of KCNA4. Rs11500237 was nearly genome-wide significant (P = 2.99 × 10−7) after meta-analysis with the replication sample.

Fig. 4

Association of stimulant dependence with SNPs located in the GNAO1 region in the African American discovery sample.SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs116441240. Rs116441240 was nearly genome-wide significant (P = 1.09 × 10−7) after meta-analysis with the replication sample.

Fig. 5

Association of stimulant dependence with SNPs located in the CPVL region in the combined African American and European ancestry discovery sample.SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes combined European and African reference panels with the top-ranked SNP, rs116441240. Rs116441240 was nearly genome-wide significant (P = 3.05 × 10−7) after meta-analysis with the replication sample.

#	Section	Preview
0	Introduction	Amphetamines have been used to treat a variety of conditions including asthma, obesity, and…
1	Introduction	The misuse of amphetamines is a public health problem. Emergency room visits related to stimulant…
2	Introduction	Family and twin studies have shown that the risk of stimulant use disorder is proportional to the…
3	Subjects and methods — Participants and diagnostic procedures	The discovery sample was derived from the Yale-Penn sample, a cohort of 11,439 participants (5758…
4	Subjects and methods — Participants and diagnostic procedures	assessment are reported elsewhere11,15. After excluding participants with missing stimulant use or…
5	Subjects and methods — Genotyping, imputation, quality control, and population substructure analysis	As described previously11, specimens from participants in the discovery sample were genotyped using…
6	Subjects and methods — Genotyping, imputation, quality control, and population substructure analysis	and individuals with a pairwise IBD estimate > 25% were assigned to the same family. Self-reported…
7	Subjects and methods — Genome-wide association analyses	Association of the DSM-IV diagnosis of stimulant dependence was evaluated using logistic regression…
8	Subjects and methods — Assessment of SNP effects on gene expression	SNPs that surpassed the significance threshold of p = 1.0 × 10−6 in the GWAS discovery dataset…
9	Subjects and methods — Pleiotropy analyses	Because > 70% of persons with stimulant use disorder have comorbid alcohol or cannabis use disorders…
10	Subjects and methods — Pathway analysis	Biological pathways were evaluated using the Enrichr software33…
11	Results — GWAS findings	There was minor p-value inflation in the AA (λ = 1.02), EA (λ = 1.038), and combined (λ = 1.041)…
12	Results — GWAS findings	(p = 5.51 × 10−6, OR = 2.73, Fig. 4). No SNPs approached the GWS level in EAs. There was strong…
13	Results — GWAS findings	analyzed separately, and the fourth symbol is for the replication dataset. In (B), the first three…
14	Results — GWAS findings	In the discovery GWAS, 59 SNPs (41 in AAs, 16 in EAs, and 2 in the meta-analysis) surpassed the…
15	Results — GWAS findings	combined with the replication datasets (p = 2.99 × 10−7 and p = 3.05 × 10−7, respectively),…
16	Results — GWAS findings	In light of the potentially shared physiological pathways between nicotinic receptors and…
17	Results — Genetic correlation of stimulant dependence with other psychiatric disorders	Table 3 shows that in AAs, stimulant dependence was significantly but modestly genetically…
18	Results — Genetic correlation of stimulant dependence with other psychiatric disorders	for stimulant dependence and ADHD in both AAs (adjusted p = 3.0 × 10−33) and EAs (adjusted p =…
19	Results — Pathway analyses	After correction for multiple testing, analyses that were seeded with the 235 top-ranked genes (p <…

Citation	PMID	DOI	Status
Amberger, JS et al., Nucleic Acids Res., 2019, OMIM.org: leveraging knowledge across phenotype-gene relationships	30445645	10.1093/nar/gky1151	Cited
Arya, R et al., Epileptic. Disord., 2017, GNAO1-associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype	28202424	10.1684/epd.2017.0888	Cited
Bamford, NS, Neuron, 2008, Repeated exposure to methamphetamine causes long-lasting presynaptic corticostriatal depression that is renormalized with drug readministration	18400166	10.1016/j.neuron.2008.01.033	Cited
Barrio-Real, L et al., J. Invest. Med., 2013, Association of a novel polymorphism of the beta2-chimaerin gene (CHN2) with smoking	23941981	10.2310/JIM.0b013e3182a32ff9	Cited
Bierut, LJ, Hum. Mol. Genet., 2007, Novel genes identified in a high-density genome wide association study for nicotine dependence	17158188	10.1093/hmg/ddl441	Cited
Bucholz, KK, 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
Calipari, ES et al., J. Neurosci., 2013, Amphetamine mechanisms and actions at the dopamine terminal revisited	23699503	10.1523/JNEUROSCI.1033-13.2013	Cited
Caloca, MJ et al., Biochem. J., 2003, Characterization of the Rac-GAP (Rac-GTPase-activating protein) activity of beta2-chimaerin, a ‘non-protein kinase C’ phorbol ester receptor	12877655	10.1042/bj20030727	Cited
Carithers, LJ, Biopreserv. Biobank., 2015, A novel approach to high-quality postmortem tissue procurement: The GTEx Project	26484571	10.1089/bio.2015.0032	Cited
Chung, D et al., PLoS. Genet., 2014, GPA: a statistical approach to prioritizing GWAS results by integrating pleiotropy and annotation	25393678	10.1371/journal.pgen.1004787	Cited
Cingolani, P, Fly, 2012, A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3	22728672	10.4161/fly.19695	Cited
Cortese, S, Lancet Psychiatry, 2018, Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis	30097390	10.1016/S2215-0366(18)30269-4	Cited
Danti, FR, Neurol. Genet., 2017, GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome	28357411	10.1212/NXG.0000000000000143	Cited
Davies, SJ, Cytogenet. Genome Res., 2004, Mapping of three translocation breakpoints associated with orofacial clefting within 6p24 and identification of new transcripts within the region	15218257	10.1159/000078008	Cited
Dong, H, BMC Psychiatry, 2017, Comparison of demographic characteristics and psychiatric comorbidity among methamphetamine-, heroin- and methamphetamine-heroin co-dependent males in Hunan, China	28499448	10.1186/s12888-017-1346-7	Cited
Edenberg, H, BMC Genet., 2005, Description of the data from the collaborative study on the genetics of alcoholism (COGA) and single-nucleotide polymorphism genotyping for genetic analysis workshop 14	16451628	10.1186/1471-2156-6-S1-S2	Primary
Ersche, KD et al., Curr. Opin. Neurobiol., 2013, Meta-analysis of structural brain abnormalities associated with stimulant drug dependence and neuroimaging of addiction vulnerability and resilience	23523373	10.1016/j.conb.2013.02.017	Cited
Fagen, ZM et al., J. Neurosci., 2007, Enhanced nicotinic receptor function and drug abuse vulnerability	17699659	10.1523/JNEUROSCI.2017-06.2007	Cited
Fergusson, DM et al., Arch. Gen. Psychiatry, 2003, Early reactions to cannabis predict later dependence	14557149	10.1001/archpsyc.60.10.1033	Cited
Gelernter, J, Biol. Psychiatry, 2014, Genomewide association study of opioid dependence and related traits: multiple associations mapped to calcium and potassium pathways	24143882	10.1016/j.biopsych.2013.08.034	Primary
Goldman, D et al., Nat., Rev. Genet., 2005, The genetics of addictions: uncovering the genes	15995696	10.1038/nrg1635	Cited
Hao, L et al., Shanghai Arch. Psychiatry, 2017, CHN2 promoter methylation change may be associated with methamphetamine dependence	29719347	10.11919/j.issn.1002-0829.217100	Cited
Harstad, E et al., Pediatrics, 2014, & Committee on Substance Abuse. Attention-deficit/hyperactivity disorder and substance abuse	24982106	10.1542/peds.2014-0992	Cited
Hart, AB et al., Curr. Top. Behav. Neurosci., 2012, Genetic factors modulating the response to stimulant drugs in humans	22261702	10.1007/7854_2011_187	Cited
Howie, B et al., Nat. Genet., 2012, Fast and accurate genotype imputation in genome-wide association studies through pre-phasing	22820512	10.1038/ng.2354	Cited
Hughes, A. et al. Prescription drug use and misuse in the United States: results from the 2015 national survey on drug use and health. NSDUH Data Rev. https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR2-2015/NSDUH-FFR2-2015.htm (2016).	—	—	—
Humphreys, KL et al., Jama. Psychiatry, 2013, Stimulant medication and substance use outcomes: a meta-analysis	23754458	10.1001/jamapsychiatry.2013.1273	Cited
Kahlig, KM, Proc. Natl Acad. Sci. USA, 2005, Amphetamine induces dopamine efflux through a dopamine transporter channel	15728379	10.1073/pnas.0407737102	Cited
Kanehisa, M et al., Nucleic Acids Res., 2000, KEGG: kyoto encyclopedia of genes and genomes	10592173	10.1093/nar/28.1.27	Cited
Kang, J et al., Eur. J. Pharm., 2003, Interactions of the narcotic l-alpha-acetylmethadol with human cardiac K+ channels	12498903	10.1016/S0014-2999(02)02700-0	Cited
Kendler, KS et al., Psychol. Med., 2005, Genetic and environmental influences on illicit drug use and tobacco use across birth cohorts	16168157	10.1017/S0033291705004964	Cited
Kest, B, Neuroscience, 2009, Gnao1 (G alphaO protein) is a likely genetic contributor to variation in physical dependence on opioids in mice	19460419	10.1016/j.neuroscience.2009.05.027	Cited
Kuleshov, MV, Nucleic Acids Res., 2016, Enrichr: a comprehensive gene set enrichment analysis web server 2016 update	27141961	10.1093/nar/gkw377	Cited
Lai, D, Genes. Brain. Behav., 2019, Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria	31090166	10.1111/gbb.12579	Primary
Lehrmann, E, PLoS. One, 2006, Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse	17205118	10.1371/journal.pone.0000114	Cited
Li, J et al., Heredity, 2005, Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix	16077740	10.1038/sj.hdy.6800717	Cited
Liu, JZ, Nat. Genet., 2010, Meta-analysis and imputation refines the association of 15q25 with smoking quantity	20418889	10.1038/ng.572	Cited
Malison, RT, Addict. Behav., 2011, Inter-rater reliability and concurrent validity of DSM-IV opioid dependence in a Hmong isolate using the Thai version of the semi-structured assessment for drug dependence and alcoholism (SSADDA)	20888699	10.1016/j.addbeh.2010.08.031	Cited
Martin, J, Biol. Psychiatry, 2018, A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder	29325848	10.1016/j.biopsych.2017.11.026	Cited
Otowa, T, Mol. Psychiatry, 2016, Meta-analysis of genome-wide association studies of anxiety disorders	26754954	10.1038/mp.2015.197	Cited
Pierucci-Lagha, A, Drug. Alcohol. Depend., 2005, Diagnostic reliability of the semi-structured assessment for drug dependence and alcoholism (SSADDA)	15896927	10.1016/j.drugalcdep.2005.04.005	Cited
Pierucci-Lagha, A, Drug. Alcohol. Depend., 2007, Reliability of DSM-IV diagnostic criteria using the semi-structured assessment for drug dependence and alcoholism (SSADDA)	17590536	10.1016/j.drugalcdep.2007.04.014	Cited
Pletscher-Frankild, S et al., Methods, 2015, DISEASES: text mining and data integration of disease-gene associations	25484339	10.1016/j.ymeth.2014.11.020	Cited
Price, AL, Nat. Genet., 2006, Principal components analysis corrects for stratification in genome-wide association studies	16862161	10.1038/ng1847	Cited
Purcell, S, Am. J. Hum. Genet., 2007, PLINK: a toolset for whole-genome association and population-based linkage analysis	17701901	10.1086/519795	Cited
Ramasamy, A, Nat. Neurosci., 2014, Genetic variability in the regulation of gene expression in ten regions of the human brain	25174004	10.1038/nn.3801	Cited
Rungnirundorn, T et al., J. Addict. Med., 2017, Sex differences in methamphetamine use and dependence in a Thai treatment center	27649265	10.1097/ADM.0000000000000262	Cited
Saitsu, H, Eur. J. Hum. Genet., 2016, Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay	25966631	10.1038/ejhg.2015.92	Cited
Salo, R, Psychiatry Res., 2011, Psychiatric comorbidity in methamphetamine dependence	21055832	10.1016/j.psychres.2010.09.014	Cited
Sara, G, Aust. N. Z. J. Psychiatry, 2012, Stimulant use disorders: characteristics and comorbidity in an Australian population sample	22990432	10.1177/0004867412461057	Cited
Seiden, LS et al., Annu. Rev. Pharmacol. Toxicol., 1993, Amphetamine: effects on catecholamine systems and behavior	8494354	10.1146/annurev.pa.33.040193.003231	Cited
Sherva, R, JAMA Psychiatry, 2016, Genome wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks	27028160	10.1001/jamapsychiatry.2016.0036	Primary
Steuer, A. E. et al. Comparative Untargeted Metabolomics Analysis of the Psychostimulants 3,4-Methylenedioxy-Methamphetamine (MDMA), Amphetamine, and the Novel Psychoactive Substance Mephedrone after Controlled Drug Administration to Humans. Metabolites10, 306 (2020).10.3390/metabo10080306PMC746548632726975	—	—	—
Substance Abuse and Mental Health Services Administration (SAMHSA), D.A.W.N., 2011: National Estimates of Drug-Related Emergency Department Visits. (Substance Abuse and Mental Health Services Administration, 2013).	—	—	—
Sulaiman, AH, Compr. Psychiatry, 2014, The risk and associated factors of methamphetamine psychosis in methamphetamine-dependent patients in Malaysia	23433219	10.1016/j.comppsych.2013.01.003	Cited
Tobacco and Genetics Consortium., Nat. Genet., 2010, Genome-wide meta-analyses identify multiple loci associated with smoking behavior	20418890	10.1038/ng.571	Cited
Toth, F., Cseh, E. K. & Vecsei, L. Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and alpha-Lipoic Acid. Int. J. Mol. Sci.22, 403 (2021).10.3390/ijms22010403PMC779578433401674	—	—	—
Uhl, GR, Arch. Gen. Psychiatry, 2008, Genome-wide association for methamphetamine dependence convergent results from 2 samples	18316681	10.1001/archpsyc.65.3.345	Cited
Uhlen, M, Science, 2017, A pathology atlas of the human cancer transcriptome	28818916	10.1126/science.aan2507	Cited
Volkow, N et al., Am. J. Psychiatry, 2008, Does childhood treatment of ADHD with stimulant medication affect substance abuse in adulthood?	18450933	10.1176/appi.ajp.2008.08020237	Cited
Vozza, A, Biochim. Biophys. Acta Bioenerg., 2017, Biochemical characterization of a new mitochondrial transporter of dephosphocoenzyme A in Drosophila melanogaster	27836698	10.1016/j.bbabio.2016.11.006	Cited
Walters, RK, Nat. Neurosci., 2018, Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders	30482948	10.1038/s41593-018-0275-1	Primary
Willer, CJ et al., Bioinformatics, 2010, METAL: fast and efficient meta-analysis of genomewide association scans	20616382	10.1093/bioinformatics/btq340	Cited
Zador, F. et al. Kynurenines and the Endocannabinoid System in Schizophrenia: Common Points and Potential Interactions. Molecules24, 3709 (2019).10.3390/molecules24203709PMC683237531619006	—	—	—
Zalewska-Kaszubska, J. et al. Voluntary alcohol consumption and plasma beta-endorphin levels in alcohol preferring rats chronically treated with lamotrigine. Physiol. Behav.139, 7–12 (2015).10.1016/j.physbeh.2014.11.02625449391	—	—	—
Zheng, J, Bioinformatics, 2017, LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis	27663502	10.1093/bioinformatics/btw613	Cited
Zhou, H, JAMA Psychiatry, 2017, Genetic risk variants associated with comorbid alcohol dependence and major depression	29071344	10.1001/jamapsychiatry.2017.3275	Cited

Title	Authors	Journal	Year	Link
Neurostructural alterations, trait impulsivity, and genetic architecture in individuals with methamphetamine dependence: a multimodal imaging-genetics study.	Luo D et al.	—	2026	→
Determining the diagnostic cut-off on the Chinese version of severity of dependence scale for DSM-5 stimulant use disorder.	Chung AKK et al.	—	2025	→
Genome data based deep learning identified new genes predicting pharmacological treatment response of attention deficit hyperactivity disorder.	Zhao Y et al.	—	2025	→
Is buprenorphine maternal dose associated with neonatal opioid withdrawal syndrome severity?	Marc B et al.	—	2025	→
Lipid metabolism in germinated tree peony (Paeonia suffruticosa Andr.) seeds: From energy mobilization to nutrient accumulation.	Xie X et al.	—	2025	→
Association between ADHD symptoms and illicit stimulants use following 1 year among French university students of the i-Share cohort.	Jean FAM et al.	—	2024	→
Genotype-by-diagnosis interaction influences self-control in human cocaine addiction.	Graczyk MM et al.	—	2023	→
The Collaborative Study on the Genetics of Alcoholism: Overview.	Agrawal A et al.	—	2023	→

Genome-wide association study of stimulant dependence.

External