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Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors
Department of Psychiatry, School of Medicine and McKnight Brain Institute, University of Florida, W University Ave., Gainesville, FL 32601, USA
Department of Engineering Management Advanced Technology, Chang Jung Christian University, No. 396, Sec. 1, Changrong Road, Tainan 71101, Taiwan
Department of Anatomy & Neurobiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
Department of Occupational Safety and Health, Chang Jung Christian University, No. 396, Sec. 1, Changrong Road, Tainan 71101, Taiwan
Emeritus, Department of Physiology, University of Tennessee, 719 Andy Holt Tower, Knoxville, TN 37996, USA
Unique Mindcare, Inc., 1900 Saint James Place, Houston, TX 77056, USA
Department of Neurofeedback, Southeastern Biofeedback and Neurobehavioral Clinic, 101 Westwood Road, Knoxville, TN 37919, USA
Department of Neuroscience & Population Genetics, EMMS Nazareth Hospital, Nazareth, Israel
Department of Neurosurgery, Weill Cornell College of Medicine, 1300 York Ave., New York, NY 10065, USA
Department of Academic Informatics Services, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
Department of Nutrigenomics, LifeGen, Inc., P.O. Box 366, 570 Lederach Stattion Way, Lederach, PA 19450, USA
Department of Genomic Research, Carlsbad Science Foundation, Department of Medical Genetics, City of Hope National Medical Center, 1500 Duarte Road, Duarte, CA 91010, USA
Department of Kinesiology and Health Sciences, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada
Department of Integrative Medicine, PATH Medical Research Foundation, 304 Park Ave. South, New York, NY 10010, USA
Hospital Universitario 12 de Octubre, Servicio de Psiquiatria, Av. Cordoba SN, Madrid 28041, Spain
Department of Holistic Medicine, G&G Holistic Addiction Treatment, Inc., 1590 Northeast 162nd Street, North Miami Beach, FL 33162, USA
Department of Research, National Institute for Holistic Addiction Studies, 1590 Northeast 162nd Street, North Miami Beach, FL 33162, USA
Dominion Diagnostics, Inc., 211 Circuit Road, North Kingstown, RI 02852, USA
Center for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur, West Bengal, India
Meadows Edge Recovery Center, 580 10 Rod Road, North Kingstown, RI 02852, USA
* Authors to whom correspondence should be addressed.
Received: 26 October 2011; in revised form: 23 November 2011 / Accepted: 23 November 2011 / Published: 29 November 2011
Abstract: Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.
Keywords: dopamine; gene polymorphisms; generational association studies; phenotype; “super normal” controls; Reward Deficiency Syndrome (RDS)
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Blum, K.; Chen, A.L.C.; Oscar-Berman, M.; Chen, T.J.H.; Lubar, J.; White, N.; Lubar, J.; Bowirrat, A.; Braverman, E.; Schoolfield, J.; Waite, R.L.; Downs, B.W.; Madigan, M.; Comings, D.E.; Davis, C.; Kerner, M.M.; Knopf, J.; Palomo, T.; Giordano, J.J.; Morse, S.A.; Fornari, F.; Barh, D.; Femino, J.; Bailey, J.A. Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors. Int. J. Environ. Res. Public Health 2011, 8, 4425-4459.
Blum K, Chen ALC, Oscar-Berman M, Chen TJH, Lubar J, White N, Lubar J, Bowirrat A, Braverman E, Schoolfield J, Waite RL, Downs BW, Madigan M, Comings DE, Davis C, Kerner MM, Knopf J, Palomo T, Giordano JJ, Morse SA, Fornari F, Barh D, Femino J, Bailey JA. Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors. International Journal of Environmental Research and Public Health. 2011; 8(12):4425-4459.
Blum, Kenneth; Chen, Amanda L. C.; Oscar-Berman, Marlene; Chen, Thomas J. H.; Lubar, Joel; White, Nancy; Lubar, Judith; Bowirrat, Abdalla; Braverman, Eric; Schoolfield, John; Waite, Roger L.; Downs, Bernard W.; Madigan, Margaret; Comings, David E.; Davis, Caroline; Kerner, Mallory M.; Knopf, Jennifer; Palomo, Tomas; Giordano, John J.; Morse, Siobhan A.; Fornari, Frank; Barh, Debmalya; Femino, John; Bailey, John A. 2011. "Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors." Int. J. Environ. Res. Public Health 8, no. 12: 4425-4459.