Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups.
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Fan CC, Bartsch H, Schork AJ, Chen CH, Wang Y, Lo MT et al. Modeling the 3D geometry of the cortical surface with genetic ancestry. Curr Biol 2015; 25: 1988–1992.
Bakken TE, Dale AM, Schork NJ. A geographic cline of skull and brain morphology among individuals of European Ancestry. Human heredity 2011; 72: 35–44.
Pfefferbaum A, Rohlfing T, Pohl KM, Lane B, Chu W, Kwon D et al. Adolescent development of cortical and white matter structure in the NCANDA sample: role of sex, ethnicity, puberty, and alcohol drinking. Cereb Cortex 2016; 26: 4101–4121.
Reyes-Centeno H, Ghirotto S, Detroit F, Grimaud-Herve D, Barbujani G, Harvati K. Genomic and cranial phenotype data support multiple modern human dispersals from Africa and a southern route into Asia. Proc Natl Acad Sci USA 2014; 111: 7248–7253.
Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011; 63: 182–217.
Heinz A, Schlagenhauf F. Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 2010; 36: 472–485.
Volkow ND, Gur RC, Wang GJ, Fowler JS, Moberg PJ, Ding YS et al. Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am J Psychiatry 1998; 155: 344–349.
Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 2009; 35: 549–562.
Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O et al. Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci 2002; 5: 169–174.
Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE et al. Effect of social status on striatal dopamine D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse 1998; 29: 80–83.
Martinez D, Orlowska D, Narendran R, Slifstein M, Liu F, Kumar D et al. Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers. Biol Psychiatry 2010; 67: 275–278.
Nader MA, Nader SH, Czoty PW, Riddick NV, Gage HD, Gould RW et al. Social dominance in female monkeys: dopamine receptor function and cocaine reinforcement. Biol Psychiatry 2012; 72: 414–421.
Wiers CE, Shokri-Kojori E, Cabrera E, Cunningham S, Wong C, Tomasi D et al. Socioeconomic status is associated with striatal dopamine D2/D3 receptors in healthy volunteers but not in cocaine abusers. Neurosci Lett 2016; 617: 27–31.
Volkow ND, Morales M. The brain on drugs: from reward to addiction. Cell 2015; 162: 712–725.
Volkow ND, Baler RD. NOW vs LATER brain circuits: implications for obesity and addiction. Trends Neurosci 2015; 38: 345–352.
Volkow ND, Logan J, Fowler JS, Wang GJ, Gur RC, Wong C et al. Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism. Am J Psychiatry 2000; 157: 75–80.
Ishibashi K, Ishii K, Oda K, Kawasaki K, Mizusawa H, Ishiwata K. Regional analysis of age-related decline in dopamine transporters and dopamine D2-like receptors in human striatum. Synapse 2009; 63: 282–290.
Wiers CE, Shumay E, Cabrera E, Shokri-Kojori E, Gladwin TE, Skarda E et al. Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers. Transl Psychiatry 2016; 6: e752.
Volkow ND, Tomasi D, Wang GJ, Telang F, Fowler JS, Logan J et al. Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain. J Neurosci 2012; 32: 6711–6717.
Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Wong C et al. Sleep deprivation decreases binding of [11C]raclopride to dopamine D2/D3 receptors in the human brain. J Neurosci 2008; 28: 8454–8461.
Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Zald DH. Associations between dopamine D2 receptor availability and BMI depend on age. NeuroImage 2016; 138: 176–183.
Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W et al. Brain dopamine and obesity. Lancet 2001; 357: 354–357.
Borg J, Cervenka S, Kuja-Halkola R, Matheson GJ, Jonsson EG, Lichtenstein P et al. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain. Mol Psychiatry 2016; 21: 1077–1084.
Smith CT, Dang LC, Buckholtz JW, Tetreault AM, Cowan RL, Kessler RM et al. The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum. Transl Psychiatry 2017; 7: e1091.
Gluskin BS, Mickey BJ. Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies. Transl Psychiatry 2016; 6: e747.
Eisenstein SA, Bogdan R, Love-Gregory L, Corral-Frias NS, Koller JM, Black KJ et al. Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. Synapse 2016; 70: 418–431.
Gelernter J, Goldman D, Risch N. The A1 allele at the D2 dopamine receptor gene and alcoholism. A reappraisal. JAMA 1993; 269: 1673–1677.
Tomasi D, Wang GJ, Wang R, Caparelli EC, Logan J, Volkow ND. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors. Human Brain Map 2015; 36: 120–136.
Volkow ND, Tomasi D, Wang GJ, Logan J, Alexoff DL, Jayne M et al. Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers. Mol Psychiatry 2014; 19: 1037–1043.
Wiers CE, Cabrera EA, Tomasi D, Wong CT, Demiral SB, Kim SW et al. Striatal dopamine D2/D3 receptor availability varies across smoking status. Neuropsychopharmacology 2017; 42: 2325–2332.
Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci USA 2014; 111: E3149–E3156.
Ducci F, Roy A, Shen PH, Yuan Q, Yuan NP, Hodgkinson CA et al. Association of substance use disorders with childhood trauma but not African genetic heritage in an African American cohort. Am J Psychiatry 2009; 166: 1031–1040.
Enoch MA, Shen PH, Xu K, Hodgkinson C, Goldman D. Using ancestry-informative markers to define populations and detect population stratification. J Psychopharmacol 2006; 20(4 Suppl): 19–26.
Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA et al. Genetic structure of human populations. Science 2002; 298: 2381–2385.
Conrad DF, Jakobsson M, Coop G, Wen X, Wall JD, Rosenberg NA et al. A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet 2006; 38: 1251–1260.
Volkow ND, Fowler JS, Wolf AP, Schlyer D, Shiue CY, Alpert R et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 1990; 147: 719–724.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Gifford A et al. Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 1999; 156: 1440–1443.
Wang GJ, Volkow ND, Fowler JS, Logan J, Abumrad NN, Hitzemann RJ et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology 1997; 16: 174–182.
Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996; 16: 834–840.
Shu WY, Li JL, Wang XD, Huang M. Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population. Acta Pharmacol Sin 2015; 36: 535–543.
Taylor B, Moffett BS, Krenek M, Valdes SO, Kim J. Race contributes to beta-blocker efficacy in pediatric patients with arrhythmias. Pediatr Cardiol 2014; 35: 641–644.
Glazer WM, Morgenstern H, Doucette J. Race and tardive dyskinesia among outpatients at a CMHC. Hosp Comm Psychiatry 1994; 45: 38–42.
Wonodi I, Reeves G, Carmichael D, Verovsky I, Avila MT, Elliott A et al. Tardive dyskinesia in children treated with atypical antipsychotic medications. Mov Disord 2007; 22: 1777–1782.
Tenback DE, van Harten PN, van Os J. Non-therapeutic risk factors for onset of tardive dyskinesia in schizophrenia: a meta-analysis. Mov Disord 2009; 24: 2309–2315.
Zai CC, Romano-Silva MA, Hwang R, Zai GC, Deluca V, Muller DJ et al. Genetic study of eight AKT1 gene polymorphisms and their interaction with DRD2 gene polymorphisms in tardive dyskinesia. Schizophr Res 2008; 106: 248–252.
Mickey BJ, Sanford BJ, Love TM, Shen PH, Hodgkinson CA, Stohler CS et al. Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans. J Neurosci 2012; 32: 9344–9350.
Burghardt PR, Love TM, Stohler CS, Hodgkinson C, Shen PH, Enoch MA et al. Leptin regulates dopamine responses to sustained stress in humans. J Neurosci 2012; 32: 15369–15376.
Tiihonen J, Rautiainen MR, Ollila HM, Repo-Tiihonen E, Virkkunen M, Palotie A et al. Genetic background of extreme violent behavior. Mol Psychiatry 2015; 20: 786–792.
Oyama S, Terry SF. Epigenetics and racial health inequities. Genet Test Mol Biomark 2016; 20: 483–484.
Kaufman JS, Cooper RS, McGee DL. Socioeconomic status and health in blacks and whites: the problem of residual confounding and the resiliency of race. Epidemiology (Cambridge, Mass) 1997; 8: 621–628.
Jupp B, Murray JE, Jordan ER, Xia J, Fluharty M, Shrestha S et al. Social dominance in rats: effects on cocaine self-administration, novelty reactivity and dopamine receptor binding and content in the striatum. Psychopharmacology 2015; 233: 579–8.
Cooper RS, Kennelly JF, Durazo-Arvizu R, Oh HJ, Kaplan G, Lynch J. Relationship between premature mortality and socioeconomic factors in black and white populations of US metropolitan areas. Public Health Rep 2001; 116: 464–473.
Cooper RS, Kaufman JS, Ward R. Race and genomics. N Engl J Med 2003; 348: 1166–1170.
Cooper RS. Race in biological and biomedical research. Cold Spring Harb Perspect Med 2013; 3: a008573.
Kaufman JS, Cooper RS. Seeking causal explanations in social epidemiology. Am J Epidemiol 1999; 150: 113–120.
Kogler L, Muller VI, Chang A, Eickhoff SB, Fox PT, Gur RC et al. Psychosocial versus physiological stress - Meta-analyses on deactivations and activations of the neural correlates of stress reactions. NeuroImage 2015; 119: 235–251.
The work was supported by the National Institutes of Health Intramural Research Program (Y1AA-3009 to NDV). We thank Dr. Richard Cooper and Dr. Eliseo Pérez-Stable for helpful comments and suggested literature.
Conflict of Interest
The authors declare no conflict of interest.
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Wiers, C.E., Towb, P.C., Hodgkinson, C.A. et al. Association of genetic ancestry with striatal dopamine D2/D3 receptor availability. Mol Psychiatry 23, 1711–1716 (2018) doi:10.1038/mp.2017.208
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