Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability
Open accessAbstract
Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [(11)C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.
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Variants of PER2 are associated with D2 receptor availability and cocaine addiction vulnerability, risky alcohol drinking under high psychosocial stress, and disrupted sleep.
“Variants of PER2 are associated with D2 receptor availability and cocaine addiction vulnerability (133,134); risky alcohol drinking under high psychosocial stress (135); and disrupted sleep (136).”
From Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents (2018) · cites this paper as [133]
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Cites
Genetics in geographically structured populations: defining, estimating and interpreting FST
Holsinger, K. E., & Weir, B. S. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2611 · Cited by 1,422 · see citing works
Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex
Volkow, N. D. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.3.318 · Cited by 1,240 · see citing works
Self-citationNucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement
Dalley, J. W., Fryer, T. D., Brichard, L., Robinson, E. S. J., Theobald, D. E. H., Lääne, K., Peña, Y., Murphy, E. R., Shah, Y., Probst, K., et al. (2007) · Science · doi:10.1126/science.1137073 · Cited by 1,188 · see citing works
The genetics of addictions: uncovering the genes
Goldman, D., Oroszi, G., & Ducci, F. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1635 · Cited by 1,099 · see citing works
Hardy-Weinberg Equilibrium Testing of Biological Ascertainment for Mendelian Randomization Studies
Rodrı́guez, S., Gaunt, T. R., & Day, I. N. M. (2009) · American Journal of Epidemiology · doi:10.1093/aje/kwn359 · Cited by 1,050 · see citing works
Addiction: Beyond dopamine reward circuitry
Volkow, N. D., Wang, G.-J., Fowler, J. S., Tomasi, D., & Telang, F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010654108 · Cited by 959 · see citing works
Self-citationVolkow, N. D., Fowler, J. S., Wang, G., Hitzemann, R., Logan, J., Schlyer, D. J., Dewey, S. L., & Wolf, A. P. (1993) · Synapse · doi:10.1002/syn.890140210 · Cited by 924 · see citing works
Self-citationMania-like behavior induced by disruption of <i>CLOCK</i>
Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S. J., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609625104 · Cited by 803 · see citing works
Day, M., Wang, Z., Ding, J., An, X., Ingham, C. A., Shering, A. F., Wokosin, D., Ilijic, E., Sun, Z., Sampson, A. R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1632 · Cited by 745 · see citing works
Signals of recent positive selection in a worldwide sample of human populations
Pickrell, J. K., Coop, G., Novembre, J., Kudaravalli, S., Li, J. Z., Absher, D., Srinivasan, B. S., Barsh, G. S., Myers, R. M., Feldman, M. W., et al. (2009) · Genome Research · doi:10.1101/gr.087577.108 · Cited by 717 · see citing works
Variable tandem repeats accelerate evolution of coding and regulatory sequences
Gemayel, R., Vinces, M. D., Legendre, M., & Verstrepen, K. J. (2010) · Annual Review of Genetics · doi:10.1146/annurev-genet-072610-155046 · Cited by 633 · see citing works
Drug addiction: the neurobiology of behaviour gone awry
Volkow, N. D., & Li, T. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1539 · Cited by 620 · see citing works
Self-citationAddiction circuitry in the human brain
Volkow, N. D., Wang, G.-J., Fowler, J. S., & Tomasi, D. (2012) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134625 · Cited by 592 · see citing works
Self-citationMapping determinants of human gene expression by regional and genome-wide association
Cheung, V. G., Spielman, R. S., Ewens, K. G., Weber, T. M., Morley, M. P., & Burdick, J. T. (2005) · Nature · doi:10.1038/nature04244 · Cited by 588 · see citing works
From evolutionary genetics to human immunology: how selection shapes host defence genes
Barreiro, L. B., & Quintana‐Murci, L. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2698 · Cited by 556 · see citing works
Food and Drug Reward: Overlapping Circuits in Human Obesity and Addiction
Volkow, N. D., Wang, G. J., Fowler, J. S., Tomasi, D., & Baler, R. (2011) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2011_169 · Cited by 525 · see citing works
Self-citationCircadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation
Miller, B. H., McDearmon, E. L., Panda, S., Hayes, K. R., Zhang, J., Andrews, J. L., Antoch, M. P., Walker, J. R., Esser, K. A., Hogenesch, J. B., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611724104 · Cited by 509 · see citing works
D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes
Noble, E. P. (2003) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.10005 · Cited by 501 · see citing works
Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction
Wise, R. A. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.06.004 · Cited by 500 · see citing works
Cocaine sensitization and reward are under the influence of circadian genes and rhythm
Abarca, C., Albrecht, U., & Spanagel, R. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.142039099 · Cited by 472 · see citing works
Recent acceleration of human adaptive evolution
Hawks, J., Wang, E. T., Cochran, G. M., Harpending, H. C., & Moyzis, R. K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707650104 · Cited by 471 · see citing works
Effects of chronic cocaine abuse on postsynaptic dopamine receptors
(1990) · American Journal of Psychiatry · doi:10.1176/ajp.147.6.719 · Cited by 421 · see citing works
Lynch, V. J., Leclerc, R. D., May, G. E., & Wagner, G. P. (2011) · Nature Genetics · doi:10.1038/ng.917 · Cited by 413 · see citing works
Volkow, N. D., Wang, G.-J., Fowler, J. S., Logan, J., Gatley, S. J., Gifford, A., Hitzemann, R., Ding, Y.-S., & Pappas, N. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.9.1440 · Cited by 406 · see citing works
Self-citationVolkow, N. D., Wang, G.-J., Fowler, J. S., Hitzemann, R., Angrist, B., Gatley, S. J., Logan, J., Ding, Y.-S., & Pappas, N. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.1.19 · Cited by 405 · see citing works
Self-citationLee, B., London, E. D., Poldrack, R. A., Farahi, J., Nacca, A., Monterosso, J. R., Mumford, J. A., Bokarius, A. V., Dahlbom, M., Mukherjee, J., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3765-09.2009 · Cited by 374 · see citing works
Transposable elements: powerful facilitators of evolution
Oliver, K. R., & Greene, W. K. (2009) · BioEssays · doi:10.1002/bies.200800219 · Cited by 310 · see citing works
Regulation of BMAL1 Protein Stability and Circadian Function by GSK3β-Mediated Phosphorylation
Sahar, S., Zocchi, L., Kinoshita, C., Borrelli, E., & Sassone‐Corsi, P. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008561 · Cited by 291 · see citing works
Castañeda, T. R., de Prado, B. M., Prieto, D., & Mora, F. (2004) · Journal of Pineal Research · doi:10.1046/j.1600-079x.2003.00114.x · Cited by 276 · see citing works
Disentangling the effects of demography and selection in human history.
Stajich, J., & Hahn, M. (2004) · Molecular biology and evolution · doi:10.1093/molbev/msh252 · Cited by 252 · see citing works
Hood, S., Cassidy, P., Cossette, M.-P., Weigl, Y., Verwey, M., Robinson, B., Stewart, J., & Amir, S. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2128-10.2010 · Cited by 246 · see citing works
Cai, Y., Liu, S., Sothern, R. B., Xu, S., & Chan, P. (2010) · European Journal of Neurology · doi:10.1111/j.1468-1331.2009.02848.x · Cited by 184 · see citing works
A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans
Carpen, J. D., von Schantz, M., Smits, M. G., Skene, D. J., & Archer, S. N. (2006) · Journal of Human Genetics · doi:10.1007/s10038-006-0060-y · Cited by 168 · see citing works
New approaches to disease mapping in admixed populations
Seldin, M. F., Paşaniuc, B., & Price, A. L. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3002 · Cited by 166 · see citing works
McClung, C. A., Nestler, E. J., & Zachariou, V. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0062-05.2005 · Cited by 163 · see citing works
Sukumaran, S., Almon, R. R., DuBois, D. C., & Jusko, W. J. (2010) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2010.05.009 · Cited by 160 · see citing works
Clines in clock genes: fine-tuning circadian rhythms to the environment
Kyriacou, C. P., Peixoto, A. A., Sandrelli, F., Costa, R., & Tauber, E. (2008) · Trends in Genetics · doi:10.1016/j.tig.2007.12.003 · Cited by 154 · see citing works
Moyer, R. A., Wang, D., Papp, A. C., Smith, R. M., Duque, L., Mash, D. C., & Sadée, W. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.208 · Cited by 146 · see citing works
Argonaute 2 in dopamine 2 receptor–expressing neurons regulates cocaine addiction
Schaefer, A., Im, H., Venø, M. T., Fowler, C. D., Min, A. K., Intrator, A., Kjems, J., Kenny, P. J., O’Carroll, D., & Greengard, P. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20100451 · Cited by 146 · see citing works
Dopamine receptor-mediated regulation of neuronal “clock” gene expression
Imbesi, M., Yildiz, S., Arslan, A. D., Sharma, R., Manev, H., & Uz, T. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.10.044 · Cited by 141 · see citing works
Volkow, N. D., Wang, G., Fowler, J. S., Logan, J., Gatley, S. J., MacGregor, R. R., Schlyer, D. J., HITZEMANN, R. J., & Wolf, A. P. (1996) · Psychiatry Research Neuroimaging · doi:10.1016/0925-4927(96)02809-0 · Cited by 140 · see citing works
Self-citationPER2 variantion is associated with depression vulnerability
Lavebratt, C., Sjöholm, L. K., Partonen, T., Schalling, M., & Forsell, Y. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31021 · Cited by 125 · see citing works
Gene × Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction
Alia‐Klein, N., Parvaz, M. A., Woicik, P. A., Konova, A. B., Maloney, T., Shumay, E., Wang, R., Telang, F., Biegon, A. R., Wang, G., et al. (2011) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.10 · Cited by 105 · see citing works
Self-citationLewis and Fischer rats: a comparison of dopamine transporter and receptors levels
Flores, G., Wood, G. K., Barbeau, D., et al. (1998) · Brain Research · doi:10.1016/s0006-8993(98)01011-7 · Cited by 95 · see citing works
Human Population Differentiation Is Strongly Correlated with Local Recombination Rate
Keinan, A., & Reich, D. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000886 · Cited by 92 · see citing works
Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters
Von Schantz, M. (2008) · Journal of Genetics · doi:10.1007/s12041-008-0074-7 · Cited by 85 · see citing works
Bruguerolle, B., & Simon, N. (2002) · Clinical Neuropharmacology · doi:10.1097/00002826-200207000-00002 · Cited by 83 · see citing works
Electroencephalographic Sleep And Mood During Cocaine Withdrawal
Kowatch, R. A., Schnoll, S. S., Knisely, J. S., Green, D., & Elswick, R. K. (1992) · Journal of Addictive Diseases · doi:10.1300/j069v11n04_03 · Cited by 74 · see citing works
Regulation of psychostimulant‐induced signaling and gene expression in the striatum
McGinty, J. F., Shi, X., Schwendt, M., Saylor, A. J., & Toda, S. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05240.x · Cited by 66 · see citing works
Calculation and Use of the Hardy‐Weinberg Model in Association Studies
Ryckman, K. K., & Williams, S. M. (2008) · Current Protocols in Human Genetics · doi:10.1002/0471142905.hg0118s57 · Cited by 58 · see citing works
Ballon, N., Leroy, S., Roy, C., Bourdel, M., Olié, J., Charles‐Nicolas, A., Krebs, M., & Poirier, M. F. (2007) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30540 · Cited by 45 · see citing works
Sleep architecture, cocaine and visual learning
MORGAN, P. T., Pace-Schott, E. F., Sahul, Z. H., Coric, V., Stickgold, R., & Malison, R. T. (2008) · Addiction · doi:10.1111/j.1360-0443.2008.02233.x · Cited by 43 · see citing works
Association study between the DAT1, DBH and DRD2 genes and cocaine dependence in a Spanish sample
Noèlia Fernàndez-castillo, A., Ribasés, M., Roncero, C., Casas, M., Gonzalvo, B., & Cormand, B. (2010) · Psychiatric Genetics · doi:10.1097/ypg.0b013e32833b6320 · Cited by 42 · see citing works
Lohoff, F. W., Bloch, P. J., Hodge, R., Nall, A. H., Ferraro, T. N., Kampman, K. M., Dackis, C. A., O’Brien, C. P., Pettinati, H. M., & Oslin, D. W. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.02.021 · Cited by 34 · see citing works
Cruciani, F., Trombetta, B., Labuda, D., Modiano, D., Torroni, A., Costa, R., & Scozzari, R. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.105 · Cited by 33 · see citing works
Malison, R. T., Kranzler, H. R., Yang, B., & Gelernter, J. E. (2006) · Psychiatric Genetics · doi:10.1097/01.ypg.0000242198.59020.ca · Cited by 28 · see citing works
Gene – environment interactions determine the individual variability in cocaine self-administration
van der Kam, E. L., Ellenbroek, B. A., & Cools, A. R. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.12.014 · Cited by 20 · see citing works
Yuferov, V. P., Bart, G. B., & Kreek, M. J. (2005) · Nature Medicine · doi:10.1038/nm0105-23 · Cited by 19 · see citing works
A cline in the Drosophila melanogaster period gene in Australia: neither down nor under
Kyriacou, C. P., Peixoto, A. A., & Costa, R. A. (2007) · Journal of Evolutionary Biology · doi:10.1111/j.1420-9101.2007.01352.x · Cited by 15 · see citing works
Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype
Shichi, D., Ôta, M., Katsuyama, Y., et al. (2009) · Journal of Human Genetics · doi:10.1038/jhg.2009.15 · Cited by 2 · see citing works
A coalescent simulation of marker selection strategy for candidate gene association studies
Cole, S., & Long, J. C. (2007) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30564 · Cited by 2 · see citing works
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Logan, R. W., Hasler, B. P., Forbes, E. E., Franzen, P. L., Torregrossa, M. M., Huang, Y. H., Buysse, D. J., Clark, D. B., & McClung, C. A. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.11.035 · Cited by 194 · see citing works
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Logan, R. W., Parekh, P. K., Kaplan, G. N., Becker-Krail, D. D., Williams, W. P., Yamaguchi, S., Yoshino, J., Shelton, M. A., Zhu, X., Zhang, H., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0061-1 · Cited by 48 · see citing works
- Authors
- Shumay, E., Fowler, J. S., Wang, G.-J., Logan, J., Alia-Klein, N., Goldstein, R. Z., Maloney, T., Wong, C., & Volkow, N. D.
- Affiliations
- Brookhaven National Laboratory (US)
- National Institute on Drug Abuse (US)
- Corresponding author
- Shumay, E
- Venue
- Translational Psychiatry
- Published
- 2012-03-06
- Volume
- 2
- Issue
- 3
- Pages
- e86-e86
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3309530
- OpenAlex
- W1966341378
- Cited by
- 79
- References
- 61
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 8 · 2014: 6 · 2013: 5
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Drug Abuse (KO1 DA025280, R01DA023579, K01DA025280)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- cocaine dependence, variable number tandem repeat polymorphism, clock genes, striatum, genetic susceptibility to addiction, African Americans, ethnic differences in allele frequency, [11C]raclopride PET
- MeSH terms
- Adult, Alleles, Asian, Black or African American, Corpus Striatum, Female, Gene Frequency, Genetic Markers, Genetics, Population, Genotype, Genetic Carrier Screening, Hispanic or Latino, Homozygote, Humans, Male, Polymorphism, Genetic, Genetic Variation, Receptors, Dopamine D2, Minisatellite Repeats, Cocaine-Related Disorders, Genetic Predisposition to Disease, Computers, Molecular, White People, Positron-Emission Tomography, Period Circadian Proteins
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