|
1
|
Blum K, Gold MS, Cadet JL, Gondre-Lewis MC, McLaughlin T, Braverman ER, Elman I, Paul Carney B, Cortese R, Abijo T, Bagchi D, Giordano J, Dennen CA, Baron D, Thanos PK, Soni D, Makale MT, Makale M, Murphy KT, Jafari N, Sunder K, Zeine F, Ceccanti M, Bowirrat A, Badgaiyan RD. Invited Expert Opinion- Bioinformatic and Limitation Directives to Help Adopt Genetic Addiction Risk Screening and Identify Preaddictive Reward Dysregulation: Required Analytic Evidence to Induce Dopamine Homeostatsis. MEDICAL RESEARCH ARCHIVES 2023; 11:10.18103/mra.v11i8.4211. [PMID: 37885438 PMCID: PMC10601302 DOI: 10.18103/mra.v11i8.4211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Addiction, albeit some disbelievers like Mark Lewis [1], is a chronic, relapsing brain disease, resulting in unwanted loss of control over both substance and non- substance behavioral addictions leading to serious adverse consequences [2]. Addiction scientists and clinicians face an incredible challenge in combatting the current opioid and alcohol use disorder (AUD) pandemic throughout the world. Provisional data from the Centers for Disease Control and Prevention (CDC) shows that from July 2021-2022, over 100,000 individuals living in the United States (US) died from a drug overdose, and 77,237 of those deaths were related to opioid use [3]. This number is expected to rise, and according to the US Surgeon General it is highly conceivable that by 2025 approximately 165,000 Americans will die from an opioid overdose. Alcohol abuse, according to data from the World Health Organization (WHO), results in 3 million deaths worldwide every year, which represents 5.3% of all deaths globally [4].
Collapse
Affiliation(s)
- Kenneth Blum
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX., USA
- Division of Addiction Research & Education, Center for Sports, Exercise & Psychiatry, Western University Health Sciences, Pomona, CA., USA
- Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary
- Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT.,USA
- Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Centre, Dayton, OH, USA
- Division of Nutrigenomics Research, TranspliceGen Therapeutics, Inc., Austin, Tx., 78701, USA
- Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, FL, USA
- Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, CA., USA
- Sunder Foundation, Palm Springs, CA, USA
- Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, Israel
| | - Mark S Gold
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO., USA
| | - Jean Lud Cadet
- Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD., USA
| | - Marjorie C. Gondre-Lewis
- Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC., USA
| | - Thomas McLaughlin
- Division of Nutrigenomics Research, TranspliceGen Therapeutics, Inc., Austin, Tx., 78701, USA
| | - Eric R Braverman
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX., USA
| | - Igor Elman
- Center for Pain and the Brain (P.A.I.N Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, MA., USA
| | - B. Paul Carney
- Division Pediatric Neurology, University of Missouri, School of Medicine, Columbia, MO., USA
| | - Rene Cortese
- Department of Child Health – Child Health Research Institute, & Department of Obstetrics, Gynecology and Women’s Health School of Medicine, University of Missouri, MO., USA
| | - Tomilowo Abijo
- Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC., USA
| | - Debasis Bagchi
- Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy and Health Sciences, Houston, TX, USA
| | - John Giordano
- Division of Personalized Mental Illness Treatment & Research, Ketamine Infusion Clinics of South Florida, Pompano Beach, Fl., USA
| | - Catherine A. Dennen
- Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA
| | - David Baron
- Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Panayotis K Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
- Department of Psychology, State University of New York at Buffalo, Buffalo, NY 14203, USA
| | - Diwanshu Soni
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA., USA
| | - Milan T. Makale
- Department of Radiation Medicine and Applied Sciences, UC San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, USA
| | - Miles Makale
- Department of Psychology, UC San Diego, Health Sciences Drive, La Jolla, CA, 92093, USA
| | | | - Nicole Jafari
- Department of Human Development, California State University at long Beach, Long Beach, CA., USA
- Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, CA., USA
| | - Keerthy Sunder
- Department of Psychiatry, Menifee Global Medical Center, Palm Desert, CA., USA
- Sunder Foundation, Palm Springs, CA, USA
| | - Foojan Zeine
- Awareness Integration Institute, San Clemente, CA., USA
- Department of Health Science, California State University at Long Beach, Long Beach, CA., USA
| | - Mauro Ceccanti
- Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze (SITAC), ASL Roma1, Sapienza University of Rome, Rome, Italy
| | - Abdalla Bowirrat
- Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, Israel
| | - Rajendra D. Badgaiyan
- Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX., USA
- Department of Psychiatry, Mt Sinai University School of Medicine, New York, NY., USA
| |
Collapse
|
|
2
|
Elam KK, Ha T, Neale Z, Aliev F, Dick D, Lemery-Chalfant K. Age varying polygenic effects on alcohol use in African Americans and European Americans from adolescence to adulthood. Sci Rep 2021; 11:22425. [PMID: 34789846 PMCID: PMC8599703 DOI: 10.1038/s41598-021-01923-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 11/08/2021] [Indexed: 01/06/2023] Open
Abstract
Genetic effects on alcohol use can vary over time but are often examined using longitudinal models that predict a distal outcome at a single time point. The vast majority of these studies predominately examine effects using White, European American (EA) samples or examine the etiology of genetic variants identified from EA samples in other racial/ethnic populations, leading to inconclusive findings about genetic effects on alcohol use. The current study examined how genetic influences on alcohol use varied by age across a 15 year period within a diverse ethnic/racial sample of adolescents. Using a multi-ethnic approach, polygenic risk scores were created for African American (AA, n = 192) and EA samples (n = 271) based on racially/ethnically aligned genome wide association studies. Age-varying associations between polygenic scores and alcohol use were examined from age 16 to 30 using time-varying effect models separately for AA and EA samples. Polygenic risk for alcohol use was found to be associated with alcohol use from age 22-27 in the AA sample and from age 24.50 to 29 in the EA sample. Results are discussed relative to the intersection of alcohol use and developmental genetic effects in diverse populations.
Collapse
Affiliation(s)
- Kit K Elam
- Department of Applied Health Science, Indiana University, 1025 E. 7th St., Suite 116, Bloomington, IN, 47405, USA.
| | - Thao Ha
- Department of Psychology, Arizona State University, Tempe, USA
| | - Zoe Neale
- Department of Psychology, Virgina Commonwealth University, Richmond, USA
| | - Fazil Aliev
- Department of Psychology, Virgina Commonwealth University, Richmond, USA
| | - Danielle Dick
- Department of Psychology, Virgina Commonwealth University, Richmond, USA
| | | |
Collapse
|
|
3
|
Zhang C, Hu R, Zhang G, Zhe Y, Hu B, He J, Wang Z, Qi X. A Weighted Genetic Risk Score Based on Four APOE-Independent Alzheimer’s Disease Risk Loci May Supplement APOE E4 for Better Disease Prediction. J Mol Neurosci 2019; 69:433-443. [DOI: 10.1007/s12031-019-01372-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 06/26/2019] [Indexed: 12/13/2022]
|
|
4
|
Developing community-based health education strategies with family history: Assessing the association between community resident family history and interest in health education. Soc Sci Med 2019; 271:112160. [PMID: 30862375 DOI: 10.1016/j.socscimed.2019.02.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 02/01/2019] [Accepted: 02/07/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Family history (FH) is an underutilized genetically informative tool that can influence disease prevention and treatment. It is unclear how FH fits into the development of community-based health education. This study examines the role that FH plays in perceived threat and health education related to mental and chronic physical conditions in the context of the health belief model. METHODS Data were collected from 1,048 adult participants aged 18-90 years. Approximately 76% of participants indicated African-American race/ethnicity and 35% had less than high school level education. Self-report data were collected on FH of four disorders: anxiety, depression, diabetes, and high blood pressure. Interest in receiving information regarding prevention as well as future testing efforts was assessed broadly. A series of logistic regressions examined the association between FH for each of the disorders and interest in receiving information on (1) prevention of diseases in general and (2) testing for diseases in general. These associations were also analyzed after accounting for the influence of perceived threat of conditions. RESULTS Interest in receiving general health education was significantly associated with FH of depression (OR = 2.72, 95% CI = 1.74-4.25), anxiety (OR = 2.26, 95% CI = 1.45-3.22), and high blood pressure (OR = 2.54, 95% CI = 1.05-6.12). After adjustment for perceived threat, the magnitude of these associations was reduced substantially. The associations between perceived threat and either interest in receiving information on disease testing or receiving general health education were strong and significant across all conditions (OR = 2.11-3.74). DISCUSSION These results provide evidence that perceived threat mediates the association between FH and engagement with health education. Currently available health education programs may benefit from considering the role of FH in an individual's motivation for participation in health education activities alongside other factors.
Collapse
|
|
5
|
Examining interactions between genetic risk for alcohol problems, peer deviance, and interpersonal traumatic events on trajectories of alcohol use disorder symptoms among African American college students. Dev Psychopathol 2018; 30:1749-1761. [DOI: 10.1017/s0954579418000962] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AbstractNumerous studies have demonstrated that genetic and environmental factors interact to influence alcohol problems. Yet prior research has primarily focused on samples of European descent and little is known about gene–environment interactions in relation to alcohol problems in non-European populations. In this study, we examined whether and how genetic risk for alcohol problems and peer deviance and interpersonal traumatic events independently and interactively influence trajectories of alcohol use disorder symptoms in a sample of African American students across the college years (N = 1,119; Mage= 18.44 years). Data were drawn from the Spit for Science study where participants completed multiple online surveys throughout college and provided a saliva sample for genotyping. Multilevel growth curve analyses indicated that alcohol dependence genome-wide polygenic risk scores did not predict trajectory of alcohol use disorder symptoms, while family history of alcohol problems was associated with alcohol use disorder symptoms at the start of college but not with the rate of change in symptoms over time. Peer deviance and interpersonal traumatic events were associated with more alcohol use disorder symptoms across college years. Neither alcohol dependence genome-wide polygenic risk scores nor family history of alcohol problems moderated the effects of these environmental risk factors on alcohol use disorder symptoms. Our findings indicated that peer deviance and experience of interpersonal traumatic events are salient risk factors that elevate risk for alcohol problems among African American college students. Family history of alcohol problems could be a useful indicator of genetic risk for alcohol problems. Gene identification efforts with much larger samples of African descent are needed to better characterize genetic risk for alcohol use disorders, in order to better understand gene–environment interaction processes in this understudied population.
Collapse
|
|
6
|
Neale ZE, Salvatore JE, Cooke ME, Savage JE, Aliev F, Donovan KK, Hancock LC, Dick DM. The Utility of a Brief Web-Based Prevention Intervention as a Universal Approach for Risky Alcohol Use in College Students: Evidence of Moderation by Family History. Front Psychol 2018; 9:747. [PMID: 29872410 PMCID: PMC5972275 DOI: 10.3389/fpsyg.2018.00747] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 04/30/2018] [Indexed: 01/28/2023] Open
Abstract
Background: Alcohol use on college campuses is prevalent and contributes to problems that affect the health, emotional wellbeing, and academic success of college students. Risk factors, such as family history of alcohol problems, predict future alcohol problems, but less is known about their potential impact on intervention effectiveness. The purpose of this study was to examine the effect of an intervention implemented in a non-randomized sample of drinking and non-drinking college freshmen. Methods: Freshmen college students recruited for the intervention study (n = 153) completed a web-adaptation of the Brief Alcohol Screening and Intervention for College Students (BASICS) at the start of spring semester. We compared their 30-days post-intervention alcohol initiation, number of drinking days (DAYS), drinks per occasion (DRINKS), maximum drinks in 24 h (MAX24) and alcohol use disorder symptoms (AUDsx) to 151 comparison participants retrospectively matched on demographics and baseline alcohol use behaviors. We also tested baseline DRINKS, DAYS, AUDsx, MAX24, and parental family history (PFH) of alcohol problems as moderators of the effect of the intervention. Results: At follow-up, intervention participants had lower rates of AUDsx than comparison participants, especially among baseline drinkers. Among participants drinking 3+ days/month at baseline, intervention participants showed fewer DAYS at follow-up than the comparison group participants. BASICS was also associated with a decreased likelihood of initiation among baseline non-drinkers. PFH significantly interacted with treatment group, with positive PFH intervention participants reporting significantly fewer AUDsx at follow-up compared to positive PFH comparison participants. We found no evidence for an effect of the intervention on DRINKS or MAX24 in our analyses. Conclusions: Results suggest some indication that novel groups, such as non-drinkers, regular drinkers, and PFH positive students may experience benefits from BASICS. Although conclusions were limited by lack of randomization and short follow-up period, PFH positive and low to moderate drinking groups represent viable targets for future randomized studies.
Collapse
Affiliation(s)
- Zoe E Neale
- Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States.,Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
| | - Jessica E Salvatore
- Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States.,Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
| | - Megan E Cooke
- Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, United States
| | - Jeanne E Savage
- Complex Trait Genetics Lab, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Fazil Aliev
- Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States.,Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
| | - Kristen K Donovan
- Division of Student Affairs, Wellness Resource Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Linda C Hancock
- Division of Student Affairs, Wellness Resource Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Danielle M Dick
- Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States.,Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States.,College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, United States
| |
Collapse
|
|
7
|
Free will in addictive behaviors: A matter of definition. Addict Behav Rep 2018; 5:94-103. [PMID: 29450231 PMCID: PMC5800588 DOI: 10.1016/j.abrep.2017.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/11/2017] [Indexed: 01/23/2023] Open
Abstract
Certain people are at risk for using alcohol or other drugs excessively and for developing problems with their use. Their susceptibility might arise from a variety of factors, including their genetic make-up, brain chemistry, family background, personality and other psychological variables, and environmental and sociocultural variables. Moreover, after substance use has become established, there are additional cognitive-motivational variables (e.g., substance-related attentional bias) that contribute to enacting behaviors consistent with the person's motivation to acquire and use the substance. People who are at such risk are likely to choose to use addictive substances even though doing so entails negative consequences. In the sense of complete freedom from being determined by causal factors, we believe that there is no such thing as free will, but defined as ability to make choices from among multiple options, even though the choices are ultimately governed by natural processes, addicted individuals are free to choose. Although they might appear unable to exercise this kind of free will in decisions about their substance use, addictive behaviors are ultimately always goal-directed and voluntary. Such goal pursuits manifest considerable flexibility. Even some severely addicted individuals can cease their use when the value of continuing the use abruptly declines or when the subjective cost of continuing the use is too great with respect to the incentives in other areas of their lives. Formal treatment strategies (e.g., contingency management, Systematic Motivational Counseling, cognitive training) can also be used to facilitate this reversal.
Collapse
|
|
8
|
Salvatore JE, Savage JE, Barr P, Wolen AR, Aliev F, Vuoksimaa E, Latvala A, Pulkkinen L, Rose RJ, Kaprio J, Dick DM. Incorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problems. Alcohol Clin Exp Res 2018; 42:413-423. [PMID: 29121402 PMCID: PMC5785466 DOI: 10.1111/acer.13551] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 11/02/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Characterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene-by-environment (G × E) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit G × E effects. METHODS We examined these questions in the young adult FinnTwin12 sample (n = 1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p-value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the G × E analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant G × E effects in an interaction between romantic relationship status and intoxication frequency. RESULTS Contrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per-SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In G × E models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. CONCLUSIONS These findings highlight the potential utility of integrating functional genomic annotation information to increase the signal-to-noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification.
Collapse
Affiliation(s)
- Jessica E. Salvatore
- Department of Psychology, Virginia Commonwealth University, PO Box 842018, Richmond, VA 23284-2018, United States
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298, United States
| | - Jeanne E. Savage
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298, United States
| | - Peter Barr
- Department of Psychology, Virginia Commonwealth University, PO Box 842018, Richmond, VA 23284-2018, United States
| | - Aaron R. Wolen
- Center for Clinical and Translational Research, Virginia Commonwealth University, P.O. Box 980261, Richmond, VA 23298-0261, United States
| | - Fazil Aliev
- Department of Psychology, Virginia Commonwealth University, PO Box 842018, Richmond, VA 23284-2018, United States
- Faculty of Business, Karabuk University, 78050 Karabuk, Turkey
| | - Eero Vuoksimaa
- Institute for Molecular Medicine FIMM, University of Helsinki, PO Box 20 (Tukholmankatu 8), FI-00014 Helsinki, Finland
| | - Antti Latvala
- Institute for Molecular Medicine FIMM, University of Helsinki, PO Box 20 (Tukholmankatu 8), FI-00014 Helsinki, Finland
| | - Lea Pulkkinen
- Department of Psychology, University of Jyväskylä, PO Box 35, 40014 University of Jyväskylä, Jyväskylä, Finland
| | - Richard J. Rose
- Department of Psychological & Brain Sciences, Indiana University, 1101 E. 10th St., Bloomington, IN 47405, United States
| | - Jaakko Kaprio
- Institute for Molecular Medicine FIMM, University of Helsinki, PO Box 20 (Tukholmankatu 8), FI-00014 Helsinki, Finland
| | - Danielle M. Dick
- Department of Psychology, Virginia Commonwealth University, PO Box 842018, Richmond, VA 23284-2018, United States
| |
Collapse
|
|
9
|
Chen J, Hutchison KE, Bryan AD, Filbey FM, Calhoun VD, Claus ED, Lin D, Sui J, Du Y, Liu J. Opposite Epigenetic Associations With Alcohol Use and Exercise Intervention. Front Psychiatry 2018; 9:594. [PMID: 30498460 PMCID: PMC6249510 DOI: 10.3389/fpsyt.2018.00594] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 10/26/2018] [Indexed: 12/31/2022] Open
Abstract
Alcohol use disorder (AUD) is a devastating public health problem in which both genetic and environmental factors play a role. Growing evidence supports that epigenetic regulation is one major mechanism in neuroadaptation that contributes to development of AUD. Meanwhile, epigenetic patterns can be modified by various stimuli including exercise. Thus, it is an intriguing question whether exercise can lead to methylation changes that are opposite to those related to drinking. We herein conducted a comparative study to explore this issue. Three cohorts were profiled for DNA methylation (DNAm), including a longitudinal exercise intervention cohort (53 healthy participants profiled at baseline and after a 12-months exercise intervention), a cross-sectional case-control cohort (81 hazardous drinkers and 81 healthy controls matched in age and sex), and a cross-sectional binge drinking cohort (281 drinkers). We identified 906 methylation sites showing significant DNAm differences between drinkers and controls in the case-control cohort, as well as, associations with drinking behavior in the drinking cohort. In parallel, 341 sites were identified for significant DNAm alterations between baseline and follow-up in the exercise cohort. Thirty-two sites overlapped between these two set of findings, of which 15 sites showed opposite directions of DNAm associations between exercise and drinking. Annotated genes of these 15 sites were enriched in signaling pathways related to synaptic plasticity. In addition, the identified methylation sites significantly associated with impaired control over drinking, suggesting relevance to neural function. Collectively, the current findings provide preliminary evidence that exercise has the potential to partially reverse DNAm differences associated with drinking at some CpG sites, motivating rigorously designed longitudinal studies to better characterize epigenetic effects with respect to prevention and intervention of AUD.
Collapse
Affiliation(s)
- Jiayu Chen
- The Mind Research Network, Albuquerque, NM, United States
| | - Kent E Hutchison
- The Mind Research Network, Albuquerque, NM, United States.,Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO, United States
| | - Angela D Bryan
- Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO, United States
| | - Francesca M Filbey
- Center for BrainHealth, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
| | - Vince D Calhoun
- The Mind Research Network, Albuquerque, NM, United States.,Department of Electrical Engineering, University of New Mexico, Albuquerque, NM, United States
| | - Eric D Claus
- The Mind Research Network, Albuquerque, NM, United States
| | - Dongdong Lin
- The Mind Research Network, Albuquerque, NM, United States
| | - Jing Sui
- The Mind Research Network, Albuquerque, NM, United States.,Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Yuhui Du
- The Mind Research Network, Albuquerque, NM, United States.,School of Computer & Information Technology, Shanxi University, Taiyuan, China
| | - Jingyu Liu
- The Mind Research Network, Albuquerque, NM, United States.,Department of Electrical Engineering, University of New Mexico, Albuquerque, NM, United States
| |
Collapse
|
|
10
|
Blum K, Modestino EJ, Gondré-Lewis MC, Neary J, Siwicki D, Hauser M, Barh D, Steinberg B, Badgaiyan RD. GLOBAL OPIOID EPIDEMIC: DOOMED TO FAIL WITHOUT GENETICALLY BASED PRECISION ADDICTION MEDICINE (PAM ™): LESSONS LEARNED FROM AMERICA. PRECISION MEDICINE 2017; 2:17-22. [PMID: 29372187 PMCID: PMC5778881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
It is a reality that globally opioid deaths have soared for men and women of all social, economic status and age from heroin and fentanyl overdoses. Specifically, in the United States, deaths from narcotic overdoses have reached alarming metrics since 2010. In fact, the Fentanyl rise is driven by drug dealers who sell it as heroin or who use it to lace cocaine or to make illegal counterfeit prescription opioids. The President's Commission on the crisis has linked the death toll as equivalent to "September 11th every three weeks." In fact, The U.S. Centre for Disease Control (CDC) released data showing that opioid-related overdoses were up 15% in the first three quarters of 2016 compared to 2015. Various governmental organizations including NIDA, are actively seeking solutions. However, we argue that unless the scientific community embraces genetic addiction risk coupled with potential precision or personalized medicine to induce "dopamine homeostasis" it will fail. We now have evidence that a ten-gene and eleven single nucleotide polymorphism (SNP) panel predicts Addiction Severity Index (ASI) for both alcohol and drugs of abuse (e.g., Opioids). In a large multi-addiction centre study involving seven diverse treatment programs, the genetic addiction risk score (GARS™) was shown to have a predictive relationship with ASI-MV derived alcohol (≥ seven alleles), and other drugs (≥ 4 alleles) severity risk scores. In a number of neuroimaging studies, we also display that in both animal (bench) and abstinent Chinese severe heroin-dependent patients (bedside), BOLD dopamine activation across the brain reward circuitry revealed increases in resting state functional connectivity as well volume connectivity. It is also known that published nutrigenomic (coupling gene polymorphisms with altered KB220z) studies reveal improved clinical outcomes related to obesity.
Collapse
Affiliation(s)
- Kenneth Blum
- Department of Psychiatry, University of Florida & McKnight Brain
Institute, College of Florida, Gainesville, FL, USA
- Department of Psychiatry, Human Integrated Services Unit University
of Vermont Center for Clinical & Translational Science, College of Medicine,
Burlington, VT, USA
- Department of Clinical Neurology, Path Research Foundation, NY, NY,
USA
- Dominion Diagnostics, LLC, North Kingstown, RI, USA
- Department of Psychiatry, Wright State University, Boonshoft School
of Medicine, Dayton, OH USA
- Division of Genetic Testing, Geneus Health LLC, San Antonio, Texas,
USA
- Center for Genomics and Applied Gene Technology, Institute of
Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West
Bengal, India
- Institute of Psychology, Eötvös Loránd
University Budapest, Hungary
- Department of Psychiatry, University of Southern California, Keck
School of Medicine, Los Angeles, CA, USA
- Division of Neuroscience Based Addiction Research and Therapy, The
Shores Treatment & Recovery Center, Port t. Lucie, Fl. USA
| | | | - Marjorie C. Gondré-Lewis
- Departments of Anatomy, Psychiatry & Behavioral Sciences,
Howard University, Washington, DC, USA
| | - Jennifer Neary
- Division of Genetic Testing, Geneus Health LLC, San Antonio, Texas,
USA
| | - David Siwicki
- Division of Genetic Testing, Geneus Health LLC, San Antonio, Texas,
USA
| | - Mary Hauser
- Dominion Diagnostics, LLC, North Kingstown, RI, USA
| | - Debmalya Barh
- Center for Genomics and Applied Gene Technology, Institute of
Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West
Bengal, India
| | | | - Rajendra D. Badgaiyan
- Department of Psychiatry, Richmond University Hospital, Icahn
School of Medicine, New York, NY, USA
| |
Collapse
|
|
11
|
Bell RL, Hauser SR, Liang T, Sari Y, Maldonado-Devincci A, Rodd ZA. Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology 2017; 122:201-243. [PMID: 28215999 PMCID: PMC5659204 DOI: 10.1016/j.neuropharm.2017.02.004] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Revised: 02/02/2017] [Accepted: 02/05/2017] [Indexed: 01/21/2023]
Abstract
The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence. The focus will be on rats and in particular selectively bred rats. Brief introductions discuss various aspects of the clinical picture, which provide characteristics of individuals with alcohol use disorders (AUDs) to model in animals. Following this, multiple selectively bred rat lines will be described and evaluated in the context of animal models used to screen medications to treat AUDs. Next, common behavioral tests for drug efficacy will be discussed particularly as they relate to stages in the addiction cycle. Tables highlighting studies that have tested the effects of compounds using the respective techniques are included. Wherever possible the Tables are organized chronologically in ascending order to describe changes in the focus of research on AUDs over time. In general, high ethanol-consuming selectively bred rats have been used to test a wide range of compounds. Older studies usually followed neurobiological findings in the selected lines that supported an association with a propensity for high ethanol intake. Most of these tests evaluated the compound's effects on the maintenance of ethanol drinking. Very few compounds have been tested during ethanol-seeking and/or relapse and fewer still have assessed their effects during the acquisition of AUDs. Overall, while a substantial number of neurotransmitter and neuromodulatory system targets have been assessed; the roles of sex- and age-of-animal, as well as the acquisition of AUDs, ethanol-seeking and relapse continue to be factors and behaviors needing further study. This article is part of the Special Issue entitled "Alcoholism".
Collapse
Affiliation(s)
- Richard L Bell
- Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA.
| | - Sheketha R Hauser
- Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA
| | - Tiebing Liang
- Indiana University School of Medicine, Department of Gastroenterology, Indianapolis, IN 46202, USA
| | - Youssef Sari
- University of Toledo, Department of Pharmacology, Toledo, OH 43614, USA
| | | | - Zachary A Rodd
- Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA
| |
Collapse
|
|
12
|
Dick DM, Barr P, Guy M, Nasim A, Scott D. Review: Genetic research on alcohol use outcomes in African American populations: A review of the literature, associated challenges, and implications. Am J Addict 2017; 26:486-493. [PMID: 28240821 PMCID: PMC5884102 DOI: 10.1111/ajad.12495] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 11/18/2016] [Accepted: 12/18/2016] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND AND OBJECTIVES There have been remarkable advances in understanding genetic influences on complex traits; however, individuals of African descent have been underrepresented in genetic research. METHODS We review the limitations of existing genetic research on alcohol phenotypes in African Americans (AA) including both twin and gene identification studies, possible reasons for underrepresentation of AAs in genetic research, the implications of the lack of racially diverse samples, and special considerations regarding conducting genetic research in AA populations. RESULTS There is a marked absence of large-scale AA twin studies so little is known about the genetic epidemiology of alcohol use and problems among AAs. Individuals of African descent have also been underrepresented in gene identification efforts; however, there have been recent efforts to enhance representation. It remains unknown the extent to which genetic variants associated with alcohol use outcomes in individuals of European and African descent will be shared. Efforts to increase representation must be accompanied by careful attention to the ethical, legal, and social implications of genetic research. This is particularly true for AAs due to the history of abuse by the biomedical community and the persistent racial discrimination targeting this population. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE Lack of representation in genetic studies limits our understanding of the etiological factors that contribute to substance use and psychiatric outcomes in populations of African descent and has the potential to further perpetuate health disparities. Involving individuals of diverse ancestry in discussions about genetic research will be critical to ensure that all populations benefit equally from genetic advances. (Am J Addict 2017;26:486-493).
Collapse
Affiliation(s)
- Danielle M Dick
- Department of Psychology, Virginia Commonwealth University, Richmond, Virginia
- Department of African American Studies, Virginia Commonwealth University, Richmond, Virginia
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Peter Barr
- Department of Psychology, Virginia Commonwealth University, Richmond, Virginia
- Department of African American Studies, Virginia Commonwealth University, Richmond, Virginia
| | - Mignonne Guy
- Department of African American Studies, Virginia Commonwealth University, Richmond, Virginia
| | - Aashir Nasim
- Department of African American Studies, Virginia Commonwealth University, Richmond, Virginia
| | - Denise Scott
- Department of Pediatrics and Human Genetics and Alcohol Research Center, Howard University College of Medicine, Washington, District of Columbia
| |
Collapse
|
|
13
|
Coley RL, Sims J, Carrano J. Environmental risks outweigh dopaminergic genetic risks for alcohol use and abuse from adolescence through early adulthood. Drug Alcohol Depend 2017; 175:106-118. [PMID: 28412301 DOI: 10.1016/j.drugalcdep.2017.01.042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 12/16/2016] [Accepted: 01/24/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Alcohol use is a primary public health concern, particularly among adolescents and young adults. Based on the rapidly growing field of gene-environment models, this study assessed the combined role of environmental and dopamine-related genetic correlates of early alcohol use and abuse. METHODS Multilevel growth models assessed trajectories of alcohol use and intoxication and ordered logistic regressions assessed alcohol use disorder among a sample of 12,437 youth from the nationally representative Add Health study who were followed from mid-adolescence through early adulthood. RESULTS Endogenous and exogenous stressful life events and social norms supportive of alcohol use from parents and peers were significant predictors of alcohol use, intoxication, and alcohol use disorder, with consistent patterns across males and females. In contrast, a dopamine-system genetic risk score (GRS) was not associated with alcohol use trajectories nor alcohol use disorder in early adulthood, although weak connections emerged between the GRS and growth trajectories of intoxication, indicating that higher GRS predicted more frequent episodes of intoxication during the transition to adulthood but not during adolescence or later 20s. No evidence of gene-environment interactions emerged. CONCLUSIONS Results extend a substantial body of prior research primarily assessing single genetic polymorphisms in the dopamine system, suggesting that dopaminergic GRSs may be associated with more problematic alcohol behaviors at some developmental periods, but further, that social norms and stressful life experiences are more consistent correlates of early and problematic alcohol use among youth. These environmental factors present potential targets for research manipulating contexts to identify causal pathways.
Collapse
Affiliation(s)
- Rebekah Levine Coley
- Boston College, Lynch School of Education, Department of Counseling, Developmental, and Educational Psychology, United States.
| | - Jacqueline Sims
- Boston College, Lynch School of Education, Department of Counseling, Developmental, and Educational Psychology, United States
| | - Jennifer Carrano
- University of Delaware, Department of Human Development and Family Studies, United States
| |
Collapse
|
|
14
|
Chartier KG, Thomas NS, Kendler KS. Interrelationship between family history of alcoholism and generational status in the prediction of alcohol dependence in US Hispanics. Psychol Med 2017; 47:137-147. [PMID: 27681653 PMCID: PMC5695542 DOI: 10.1017/s0033291716002105] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Both a family history of alcoholism and migration-related factors like US v. foreign nativity increase the risk for developing alcohol use disorders in Hispanic Americans. For this study, we integrated these two lines of research to test whether the relationship between familial alcoholism and alcohol dependence changes with successive generations in the United States. METHOD Data were from the waves 1 and 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Subjects self-identified Hispanic ethnicity (N = 4122; n = 1784 first, n = 1169 second, and n = 1169 third or later generation) and reported ever consuming ⩾12 drinks in a 1-year period. A family history of alcoholism was assessed in first- and second-degree relatives. Analyses predicting the number of alcohol dependence symptoms were path models. RESULTS Alcohol dependence symptoms were associated with a stronger family history of alcoholism and later generational status. There was a significant interaction effect between familial alcoholism and generational status; the relationship of familial alcoholism with alcohol dependence symptoms increased significantly with successive generations in the United States, more strongly in women than men. Acculturation partially mediated the interaction effect between familial alcoholism and generational status on alcohol dependence, although not in the expected direction. CONCLUSIONS Familial alcoholism interacted with generational status in predicting alcohol dependence symptoms in US Hispanic drinkers. This relationship suggests that heritability for alcoholism is influenced by a higher-order environmental factor, likely characterized by a relaxing of social restrictions on drinking.
Collapse
Affiliation(s)
- Karen G. Chartier
- Virginia Commonwealth University School of Social Work, Richmond, VA
- Virginia Commonwealth University School of Medicine, Department of Psychiatry, Richmond, VA
| | | | - Kenneth S. Kendler
- Virginia Commonwealth University School of Medicine, Department of Psychiatry, Richmond, VA
- Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA
- Virginia Commonwealth University School of Medicine, Department of Human and Molecular Genetics, Richmond, VA
| |
Collapse
|
|
15
|
Blum K, Downs B, Dushaj K, Li M, Braverman ER, Fried L, Waite R, Demotrovics Z, Badgaiyan RD. THE BENEFITS OF CUSTOMIZED DNA DIRECTED NUTRITION TO BALANCE THE BRAIN REWARD CIRCUITRY AND REDUCE ADDICTIVE BEHAVIORS. PRECISION MEDICINE 2016; 1:18-33. [PMID: 28066828 PMCID: PMC5210211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
DNA Customization of nutraceutical products is here. In the truest sense, "Gene Guided Precision Nutrition™" and KB220 variants (a complex mixture of amino-acids, trace metals, and herbals) are the pioneers and standard-bearers for a state of the art DNA customization. Findings by both, Kenneth Blum, Ph.D. and Ernest Noble, Ph.D. concerning the role of genes in shaping cravings and pleasure- seeking, opened the doors to comprehension of how genetics control our actions and effect our mental and physical health. Moreover, technology that is related to KB220 variants in order to reduce or eradicate excessive cravings by influencing gene expression is a cornerstone in the pioneering of the practical applications of nutrigenomics. Continuing discoveries have been an important catalyst for the evolution, expansion, and scientific recognition of the significance of nutrigenomics and its remarkable contributions to human health. Neuro-Nutrigenomics is now a very important field of scientific investigation that offers great promise to improving the human condition. In the forefront is the development of the Genetic Addiction Risk Score (GARS™), which unlike 23andMe, has predictive value for the severity of drug and alcohol abuse as well as other non-substance related addictive behaviors. While customization of neuronutrients has not yet been commercialized, there is emerging evidence that in the future, the concept will be developed and could have a significant impact in addiction medicine.
Collapse
Affiliation(s)
- Kenneth Blum
- Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
- Departments of Psychiatry & Behavioral Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
- Department of Clinical Neurology, PATH Foundation NY, New York, NY, USA
- Human Integrated Services Unit, University of Vermont Centre for Clinical & Translational Science, College of Medicine, Burlington, VT, USA
- Division of Addiction Services, Dominion Diagnostics, LLC., North Kingstown, RI, USA
- Division of Neuroscience-based Therapy, Summit Estate Recovery Center, Los Gatos, CA, USA
- The Shores Treatment & Recovery, Port Saint Lucie, FL, USA
- Department of Precision Medicine, IGENE, LLC., Austin, TX, USA
- Division of Nutrigenomics, LaVitaRDS, Draper, UT, USA
- Institute of Psychology, Eötvös Loránd University Budapest, HUNGARY
| | - B.W. Downs
- Victory Nutrition International, Lederoch, PA, USA
| | - Kristina Dushaj
- Department of Clinical Neurology, PATH Foundation NY, New York, NY, USA
| | - Mona Li
- Department of Clinical Neurology, PATH Foundation NY, New York, NY, USA
| | - Eric R. Braverman
- Department of Clinical Neurology, PATH Foundation NY, New York, NY, USA
| | - Lyle Fried
- The Shores Treatment & Recovery, Port Saint Lucie, FL, USA
| | - Roger Waite
- Division of Nutrigenomics, LaVitaRDS, Draper, UT, USA
| | | | - Rajendra D. Badgaiyan
- Department of Psychiatry, Laboratory of Molecular and Functional Imaging, University at Minnesota, Minneapolis, MN, USA
| |
Collapse
|
|
16
|
Bell RL, Hauser SR, McClintick J, Rahman S, Edenberg HJ, Szumlinski KK, McBride WJ. Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 137:41-85. [PMID: 26809998 DOI: 10.1016/bs.pmbts.2015.10.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.
Collapse
Affiliation(s)
- Richard L Bell
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
| | - Sheketha R Hauser
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jeanette McClintick
- Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana , USA
| | - Shafiqur Rahman
- Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota, USA
| | - Howard J Edenberg
- Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana , USA
| | - Karen K Szumlinski
- Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, California, USA
| | - William J McBride
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
17
|
Mamdani M, Williamson V, McMichael GO, Blevins T, Aliev F, Adkins A, Hack L, Bigdeli T, D. van der Vaart A, Web BT, Bacanu SA, Kalsi G, Kendler KS, Miles MF, Dick D, Riley BP, Dumur C, Vladimirov VI. Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence. PLoS One 2015; 10:e0137671. [PMID: 26381263 PMCID: PMC4575063 DOI: 10.1371/journal.pone.0137671] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 08/05/2015] [Indexed: 11/18/2022] Open
Abstract
Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
Collapse
Affiliation(s)
- Mohammed Mamdani
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Vernell Williamson
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Gowon O. McMichael
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Tana Blevins
- Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Fazil Aliev
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Amy Adkins
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Laura Hack
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Tim Bigdeli
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Andrew D. van der Vaart
- Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Bradley Todd Web
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Silviu-Alin Bacanu
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Gursharan Kalsi
- Department of Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, London SE5 8AF, United Kingdom
| | | | - Kenneth S. Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Michael F. Miles
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Danielle Dick
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Brien P. Riley
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Catherine Dumur
- Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Vladimir I. Vladimirov
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America
- Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, United States of America
- Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, United States of America
| |
Collapse
|
|
18
|
Blum K, Hauser M, Fratantonio J, Badgaiyan RD. Molecular Genetic Testing in Pain and Addiction: Facts, Fiction and Clinical Utility. ACTA ACUST UNITED AC 2015; 2:1-5. [PMID: 26807291 DOI: 10.1515/addge-2015-0001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors as well as altered pain tolerance. While there are many studies claiming a genetic association with addiction and other behavioral infractions, defined as Reward Deficiency Syndrome (RDS), not all are scientifically accurate and in some case just wrong. Albeit our bias, we discuss herein the facts and fictions behind molecular genetic testing in RDS (including pain and addiction) and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one's genetic risk for RDS.
Collapse
Affiliation(s)
- Kenneth Blum
- Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Mary Hauser
- Divisions of Addiction Services, Dominion Diagnostics,LLC, North Kingstown, RI, USA
| | - James Fratantonio
- Divisions of Applied Clinical Research & Education, Dominion Diagnostics, LLC, North Kingstown, RI, USA
| | | |
Collapse
|
|
19
|
Hart AB, Kranzler HR. Alcohol Dependence Genetics: Lessons Learned From Genome-Wide Association Studies (GWAS) and Post-GWAS Analyses. Alcohol Clin Exp Res 2015; 39:1312-27. [PMID: 26110981 PMCID: PMC4515198 DOI: 10.1111/acer.12792] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 05/26/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Alcohol dependence (AD) is a complex psychiatric disorder and a significant public health problem. Twin and family-based studies have consistently estimated its heritability to be approximately 50%, and many studies have sought to identify specific genetic variants associated with susceptibility to AD. These studies have been primarily linkage or candidate gene based and have been mostly unsuccessful in identifying replicable risk loci. Genome-wide association studies (GWAS) have improved the detection of specific loci associated with complex traits, including AD. However, findings from GWAS explain only a small proportion of phenotypic variance, and alternative methods have been proposed to investigate the associations that do not meet strict genome-wide significance criteria. METHODS This review summarizes all published AD GWAS and post-GWAS analyses that have sought to exploit GWAS data to identify AD-associated loci. RESULTS Findings from AD GWAS have been largely inconsistent, with the exception of variants encoding the alcohol-metabolizing enzymes. Analyses of GWAS data that go beyond standard association testing have demonstrated the polygenic nature of AD and the large contribution of common variants to risk, nominating novel genes and pathways for AD susceptibility. CONCLUSIONS Findings from AD GWAS and post-GWAS analyses have greatly increased our understanding of the genetic etiology of AD. However, it is clear that larger samples will be necessary to detect loci in addition to those that encode alcohol-metabolizing enzymes, which may only be possible through consortium-based efforts. Post-GWAS approaches to studying the genetic influences on AD are increasingly common and could greatly increase our knowledge of both the genetic architecture of AD and the specific genes and pathways that influence risk.
Collapse
Affiliation(s)
- Amy B. Hart
- Center for Studies of Addiction, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104
| | - Henry R. Kranzler
- Center for Studies of Addiction, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104
- VISN 4 MIRECC, Philadelphia VAMC, Philadelphia, PA 19104, USA
| |
Collapse
|
|
20
|
Suchankova P, Yan J, Schwandt ML, Stangl BL, Caparelli EC, Momenan R, Jerlhag E, Engel JA, Hodgkinson CA, Egli M, Lopez MF, Becker HC, Goldman D, Heilig M, Ramchandani VA, Leggio L. The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence. Transl Psychiatry 2015; 5:e583. [PMID: 26080318 PMCID: PMC4490279 DOI: 10.1038/tp.2015.68] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 03/18/2015] [Accepted: 04/06/2015] [Indexed: 12/24/2022] Open
Abstract
The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.
Collapse
Affiliation(s)
- P Suchankova
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - J Yan
- Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - M L Schwandt
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - B L Stangl
- Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - E C Caparelli
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
| | - R Momenan
- Section on Brain Electrophysiology and Imaging, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - E Jerlhag
- Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - J A Engel
- Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - C A Hodgkinson
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - M Egli
- Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - M F Lopez
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA
| | - H C Becker
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA
- Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
- Ralph H Johnson VA Medical Center, Charleston, SC, USA
| | - D Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - M Heilig
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - V A Ramchandani
- Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - L Leggio
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA
| |
Collapse
|
|
21
|
Blum K, Thanos PK, Badgaiyan RD, Febo M, Oscar-Berman M, Fratantonio J, Demotrovics Z, Gold MS. Neurogenetics and gene therapy for reward deficiency syndrome: are we going to the Promised Land? Expert Opin Biol Ther 2015; 15:973-85. [PMID: 25974314 DOI: 10.1517/14712598.2015.1045871] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Addiction is a substantial health issue with limited treatment options approved by the FDA and as such currently available. The advent of neuroimaging techniques that link neurochemical and neurogenetic mechanisms to the reward circuitry brain function provides a framework for potential genomic-based therapies. AREAS COVERED Through candidate and genome-wide association studies approaches, many gene polymorphisms and clusters have been implicated in drug, food and behavioral dependence linked by the common rubric reward deficiency syndrome (RDS). The results of selective studies that include the role of epigenetics, noncoding micro RNAs in RDS behaviors especially drug abuse involving alcohol, opioids, cocaine, nicotine, pain and feeding are reviewed in this article. New targets for addiction treatment and relapse prevention, treatment alternatives such as gene therapy in animal models, and pharmacogenomics and nutrigenomics methods to manipulate transcription and gene expression are explored. EXPERT OPINION The recognition of the clinical benefit of early genetic testing to determine addiction risk stratification and dopaminergic agonistic, rather than antagonistic therapies are potentially the genomic-based wave of the future. In addition, further development, especially in gene transfer work and viral vector identification, could make gene therapy for RDS a possibility in the future.
Collapse
Affiliation(s)
- Kenneth Blum
- Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine , Gainesville, FL , USA
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Dick DM, Hancock LC. Integrating basic research with prevention/intervention to reduce risky substance use among college students. Front Psychol 2015; 6:544. [PMID: 25999878 PMCID: PMC4423347 DOI: 10.3389/fpsyg.2015.00544] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 04/15/2015] [Indexed: 01/17/2023] Open
Abstract
Too often basic research on etiological processes that contribute to substance use outcomes is disconnected from efforts to develop prevention and intervention programming. Substance use on college campuses is an area of concern where translational efforts that bring together basic scientists and prevention/intervention practitioners have potential for high impact. We describe an effort at a large, public, urban university in the United States to bring together researchers across the campus with expertise in college behavioral health with university administration and health/wellness practitioners to address college student substance use and mental health. The project “Spit for Science” examines how genetic and environmental influences contribute to behavioral health outcomes across the college years. We argue that findings coming out of basic research can be used to develop more tailored prevention and intervention programming that incorporates both biologically and psychosocially influenced risk factors. Examples of personalized programming suggest this may be a fruitful way to advance the field and reduce risky substance use.
Collapse
Affiliation(s)
- Danielle M Dick
- Department of Psychiatry, Virginia Commonwealth University , Richmond, VA, USA ; Department of Psychology, Virginia Commonwealth University , Richmond, VA, USA ; Department of African American Studies, Virginia Commonwealth University , Richmond, VA, USA ; Department of Human and Molecular Genetics, Virginia Commonwealth University , Richmond, VA, USA
| | - Linda C Hancock
- Division of Student Affairs, Wellness Resource Center, Virginia Commonwealth University , Richmond, VA, USA
| |
Collapse
|
|
23
|
Kapoor M, Agrawal A. Commentary: sex differences in the pathways to symptoms of alcohol use disorder: a study of opposite-sex twin pairs. Alcohol Clin Exp Res 2015; 39:950-2. [PMID: 25912665 DOI: 10.1111/acer.12736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 03/23/2015] [Indexed: 11/30/2022]
Affiliation(s)
- Manav Kapoor
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, New York
| | - Arpana Agrawal
- Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri
| |
Collapse
|
|
24
|
Salvatore JE, Aliev F, Bucholz K, Agrawal A, Hesselbrock V, Hesselbrock M, Bauer L, Kuperman S, Schuckit MA, Kramer J, Edenberg HJ, Foroud TM, Dick DM. Polygenic risk for externalizing disorders: Gene-by-development and gene-by-environment effects in adolescents and young adults. Clin Psychol Sci 2015; 3:189-201. [PMID: 25821660 PMCID: PMC4371857 DOI: 10.1177/2167702614534211] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In this project, we aimed to bring large-scale gene identification findings into a developmental psychopathology framework. Using a family-based sample, we tested whether polygenic scores for externalizing disorders-based on single nucleotide polymorphism weights derived from genome-wide association study results in adults (n = 1,249)-predicted externalizing disorders, subclinical externalizing behavior, and impulsivity-related traits adolescents (n = 248) and young adults (n = 207), and whether parenting and peer factors in adolescence moderated polygenic risk to predict externalizing disorders. Polygenic scores predicted externalizing disorders in adolescents and young adults, even after controlling for parental externalizing disorder history. Polygenic scores also predicted subclinical externalizing behavior and impulsivity traits in the adolescents and young adults. Adolescent parental monitoring and peer substance use moderated polygenic scores to predict externalizing disorders. This illustrates how state of the science genetics can be integrated with psychological science to identify how genetic risk contributes to the development of psychopathology.
Collapse
Affiliation(s)
| | - Fazil Aliev
- Department of Psychiatry, Virginia Commonwealth University
| | | | | | | | | | - Lance Bauer
- Department of Psychiatry, University of Connecticut
| | | | - Marc A Schuckit
- Department of Psychiatry, University of California-San Diego
| | - John Kramer
- Department of Psychiatry, University of Iowa
| | - Howard J Edenberg
- Department of Biochemistry and Molecular Biology, Indiana University
| | - Tatiana M Foroud
- Department of Medical and Molecular Genetics, Indiana University
| | | |
Collapse
|
|
25
|
Manzardo AM, McGuire A, Butler MG. Clinically relevant genetic biomarkers from the brain in alcoholism with representation on high resolution chromosome ideograms. Gene 2015; 560:184-94. [PMID: 25655461 DOI: 10.1016/j.gene.2015.01.064] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 01/27/2015] [Accepted: 01/30/2015] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Alcoholism arises from combined effects of multiple biological factors including genetic and non-genetic causes with gene/environmental interaction. Intensive research and advanced genetic technology has generated a long list of genes and biomarkers involved in alcoholism neuropathology. These markers reflect complex overlapping and competing effects of possibly hundreds of genes which impact brain structure, function, biochemical alcohol processing, sensitivity and risk for dependence. METHOD We compiled a tabular list of clinically relevant genetic biomarkers for alcoholism targeting expression disturbances in the human brain through an extensive search of keywords related to alcoholism, alcohol abuse, and genetics from peer reviewed medical research articles and related nationally sponsored websites. Gene symbols were then placed on high resolution human chromosome ideograms with gene descriptions in tabular form. RESULTS We identified 337 clinically relevant genetic biomarkers and candidate genes for alcoholism and alcohol-responsiveness from human brain research. Genetic biomarkers included neurotransmitter pathways associated with brain reward processes for dopaminergic (e.g., DRD2, MAOA, and COMT), serotoninergic (e.g., HTR3A, HTR1B, HTR3B, and SLC6A4), GABAergic (e.g., GABRA1, GABRA2, and GABRG1), glutaminergic (GAD1, GRIK3, and GRIN2C) and opioid (e.g., OPRM1, OPRD1, and OPRK1) pathways which presumably impact reinforcing properties of alcohol. Gene level disturbances in cellular and molecular networks impacted by alcohol and alcoholism pathology include transketolase (TKT), transferrin (TF), and myelin (e.g., MBP, MOBP, and MOG). CONCLUSIONS High resolution chromosome ideograms provide investigators, physicians, geneticists and counselors a convenient visual image of the distribution of alcoholism genetic biomarkers from brain research with alphabetical listing of genes in tabular form allowing comparison between alcoholism-related phenotypes, and clinically-relevant alcoholism gene(s) at the chromosome band level to guide research, diagnosis, and treatment. Chromosome ideograms may facilitate gene-based personalized counseling of alcohol dependent individuals and their families.
Collapse
Affiliation(s)
- Ann M Manzardo
- Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| | - Austen McGuire
- Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Merlin G Butler
- Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| |
Collapse
|
|
26
|
Blum K, Badgaiyan RD, Agan G, Fratantonio J, Simpatico T, Febo M, Haberstick BC, Smolen A, Gold MS. Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction. ACTA ACUST UNITED AC 2015; 1:65-68. [PMID: 26052557 PMCID: PMC4455960 DOI: 10.17756/jrds.2015-009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Background The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. Methods To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. Results While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. Conclusion Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one’s genetic risk for RDS.
Collapse
Affiliation(s)
- Kenneth Blum
- Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL, USA ; Department of Addiction Research & Therapy, Malibu Beach Recovery Center, Malibu Beach, CA, USA ; Divisions of Addiction Services, and Applied Clinical Research, Dominion Diagnostics, LLC, North Kingstown, RI, USA ; Department of Psychiatry, Human Integrated Services Unit University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA
| | - Rajendra D Badgaiyan
- Department of Psychiatry and Division of Neuroimaging, University of Minnesota College of Medicine, MN, USA
| | - Gozde Agan
- Divisions of Addiction Services, and Applied Clinical Research, Dominion Diagnostics, LLC, North Kingstown, RI, USA
| | - James Fratantonio
- Divisions of Addiction Services, and Applied Clinical Research, Dominion Diagnostics, LLC, North Kingstown, RI, USA
| | - Thomas Simpatico
- Department of Psychiatry, Human Integrated Services Unit University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA
| | - Marcelo Febo
- Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Brett C Haberstick
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
| | - Andrew Smolen
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
| | - Mark S Gold
- Departments of Psychiatry & Behavioral Sciences at the Keck, University of Southern California, School of Medicine, CA, USA ; Director of Research, Drug Enforcement Administration (DEA) Educational Foundation, Washington, D.C, USA
| |
Collapse
|
|
27
|
Abstract
Alcohol use and alcohol use disorders are substantially heritable. Variants in genes coding for alcohol metabolic enzymes have long been known to influence consumption. More recent studies in family-based samples have implicated GABRA2, nicotinic receptor genes such as CHRNB3, and a number of other specific single genes as associated with alcohol use disorders. The growing use of genetic analyses, in particular studies using polygenic risk scores; neurobiologic pathways; and methods for quantifying gene × gene and gene × environment interactions have also contributed to an evolving understanding of the genetic architecture of alcohol use disorders. Additionally, the study of behavioral traits associated with alcohol dependence such as impulsivity and sensation seeking, and the influences of demographic factors (i.e., sex and ethnicity) have significantly enhanced the genetics of alcoholism literature. This article provides a brief overview of the current topically relevant findings in the field to date and includes areas of research still requiring attention.
Collapse
|
|
28
|
Ma Y, Yuan W, Jiang X, Cui WY, Li MD. Updated findings of the association and functional studies of DRD2/ANKK1 variants with addictions. Mol Neurobiol 2014; 51:281-99. [PMID: 25139281 DOI: 10.1007/s12035-014-8826-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 06/01/2014] [Indexed: 02/06/2023]
Abstract
Both nicotine and alcohol addictions are severe public health hazards worldwide. Various twin and family studies have demonstrated that genetic factors contribute to vulnerability to these addictions; however, the susceptibility genes and the variants underlying them remain largely unknown. Of susceptibility genes investigated for addictions, DRD2 has received much attention. Considering new evidence supporting the association of DRD2 and its adjacent gene ankyrin repeat and kinase domain containing 1 (ANKK1) with various addictions, in this paper, we provide an updated view of the involvement of variants in DRD2 and ANKK1 in the etiology of nicotine dependence (ND) and alcohol dependence (AD) based on linkage, association, and molecular studies. This evidence shows that both genes are significantly associated with addictions; however the association with ANKK1 appears to be stronger. Thus, both more replication studies in independent samples and functional studies of some of these variants are warranted.
Collapse
Affiliation(s)
- Yunlong Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China
| | | | | | | | | |
Collapse
|
|
29
|
Manzardo AM, Gunewardena S, Wang K, Butler MG. Exon microarray analysis of human dorsolateral prefrontal cortex in alcoholism. Alcohol Clin Exp Res 2014; 38:1594-601. [PMID: 24890784 PMCID: PMC4047192 DOI: 10.1111/acer.12429] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 03/20/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. METHODS Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). RESULTS Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN), and signaling (e.g., RASGRP3, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease and development including cellular assembly and organization impacting on psychological disorders. CONCLUSIONS Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation, and signaling that targets white matter of the brain.
Collapse
Affiliation(s)
- Ann M. Manzardo
- Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, Kansas City, KS
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, KS
- Department of Biostatistics, University of Kansas School of Medicine, Kansas City, KS
| | - Kun Wang
- Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, Kansas City, KS
| | - Merlin G. Butler
- Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, Kansas City, KS
- Department of Pediatrics, University of Kansas School of Medicine, Kansas City, KS
| |
Collapse
|
|
30
|
Genetic risk prediction and neurobiological understanding of alcoholism. Transl Psychiatry 2014; 4:e391. [PMID: 24844177 PMCID: PMC4035721 DOI: 10.1038/tp.2014.29] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 03/18/2014] [Indexed: 01/08/2023] Open
Abstract
We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) was used to generate a genetic risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.
Collapse
|
|
31
|
Salvatore JE, Aliev F, Edwards AC, Evans DM, Macleod J, Hickman M, Lewis G, Kendler KS, Loukola A, Korhonen T, Latvala A, Rose RJ, Kaprio J, Dick DM. Polygenic scores predict alcohol problems in an independent sample and show moderation by the environment. Genes (Basel) 2014; 5:330-46. [PMID: 24727307 PMCID: PMC4094936 DOI: 10.3390/genes5020330] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 03/20/2014] [Accepted: 03/27/2014] [Indexed: 12/31/2022] Open
Abstract
Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants do not. In the current study, we first tested whether polygenic risk for alcohol problems-derived from genome-wide association estimates of an alcohol problems factor score from the age 18 assessment of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4304 individuals of European descent; 57% female)-predicted alcohol problems earlier in development (age 14) in an independent sample (FinnTwin12; n = 1162; 53% female). We then tested whether environmental factors (parental knowledge and peer deviance) moderated polygenic risk to predict alcohol problems in the FinnTwin12 sample. We found evidence for both polygenic association and for additive polygene-environment interaction. Higher polygenic scores predicted a greater number of alcohol problems (range of Pearson partial correlations 0.07-0.08, all p-values ≤ 0.01). Moreover, genetic influences were significantly more pronounced under conditions of low parental knowledge or high peer deviance (unstandardized regression coefficients (b), p-values (p), and percent of variance (R2) accounted for by interaction terms: b = 1.54, p = 0.02, R2 = 0.33%; b = 0.94, p = 0.04, R2 = 0.30%, respectively). Supplementary set-based analyses indicated that the individual top single nucleotide polymorphisms (SNPs) contributing to the polygenic scores were not individually enriched for gene-environment interaction. Although the magnitude of the observed effects are small, this study illustrates the usefulness of polygenic approaches for understanding the pathways by which measured genetic predispositions come together with environmental factors to predict complex behavioral outcomes.
Collapse
Affiliation(s)
- Jessica E Salvatore
- Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980126, Richmond, VA 23298, USA.
| | - Fazil Aliev
- Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980126, Richmond, VA 23298, USA.
| | - Alexis C Edwards
- Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980126, Richmond, VA 23298, USA.
| | - David M Evans
- School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
| | - John Macleod
- School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
| | - Matthew Hickman
- School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
| | - Glyn Lewis
- Division of Psychiatry, University College London, 67-73 Riding House St., London W1W 7EJ, UK.
| | - Kenneth S Kendler
- Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980126, Richmond, VA 23298, USA.
| | - Anu Loukola
- Department of Public Health, Hjelt Institute, University of Helsinki, P.O. Box 41, Helsinki FI-00014, Finland.
| | - Tellervo Korhonen
- Department of Public Health, Hjelt Institute, University of Helsinki, P.O. Box 41, Helsinki FI-00014, Finland.
| | - Antti Latvala
- Department of Public Health, Hjelt Institute, University of Helsinki, P.O. Box 41, Helsinki FI-00014, Finland.
| | - Richard J Rose
- Department of Psychological and Brain Sciences, Indiana University, 1101 East 10th St., Bloomington, IN 47405, USA.
| | - Jaakko Kaprio
- Department of Public Health, Hjelt Institute, University of Helsinki, P.O. Box 41, Helsinki FI-00014, Finland.
| | - Danielle M Dick
- Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980126, Richmond, VA 23298, USA.
| |
Collapse
|
|
32
|
Yarosh HL, Hyatt CJ, Meda SA, Jiantonio-Kelly R, Potenza MN, Assaf M, D.Pearlson G. Relationships between reward sensitivity, risk-taking and family history of alcoholism during an interactive competitive fMRI task. PLoS One 2014; 9:e88188. [PMID: 24505424 PMCID: PMC3913753 DOI: 10.1371/journal.pone.0088188] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 01/04/2014] [Indexed: 01/03/2023] Open
Abstract
Background Individuals with a positive family history for alcoholism (FHP) have shown differences from family-history-negative (FHN) individuals in the neural correlates of reward processing. FHP, compared to FHN individuals, demonstrate relatively diminished ventral striatal activation during anticipation of monetary rewards, and the degree of ventral striatal activation shows an inverse correlation with specific impulsivity measures in alcohol-dependent individuals. Rewards in socially interactive contexts relate importantly to addictive propensities, yet have not been examined with respect to how their neural underpinnings relate to impulsivity-related measures. Here we describe impulsivity measures in FHN and FHP individuals as they relate to a socially interactive functional magnetic resonance imaging (fMRI) task. Methods Forty FHP and 29 FHN subjects without histories of Axis-I disorders completed a socially interactive Domino task during functional magnetic resonance imaging and completed self-report and behavioral impulsivity-related assessments. Results FHP compared to FHN individuals showed higher scores (p = .004) on one impulsivity-related factor relating to both compulsivity (Padua Inventory) and reward/punishment sensitivity (Sensitivity to Punishment/Sensitivity to Reward Questionnaire). Multiple regression analysis within a reward-related network revealed a correlation between risk-taking (involving another impulsivity-related factor, the Balloon Analog Risk Task (BART)) and right ventral striatum activation under reward >punishment contrast (p<0.05 FWE corrected) in the social task. Conclusions Behavioral risk-taking scores may be more closely associated with neural correlates of reward responsiveness in socially interactive contexts than are FH status or impulsivity-related self-report measures. These findings suggest that risk-taking assessments be examined further in socially interactive settings relevant to addictive behaviors.
Collapse
Affiliation(s)
- Haley L. Yarosh
- Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, Connecticut, United States of America
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
| | - Christopher J. Hyatt
- Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, Connecticut, United States of America
| | - Shashwath A. Meda
- Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, Connecticut, United States of America
| | - Rachel Jiantonio-Kelly
- Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, Connecticut, United States of America
| | - Marc N. Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Child Study Center, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Michal Assaf
- Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, Connecticut, United States of America
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Godfrey D.Pearlson
- Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, Connecticut, United States of America
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| |
Collapse
|
|
33
|
Schuckit MA. A brief history of research on the genetics of alcohol and other drug use disorders. J Stud Alcohol Drugs Suppl 2014; 75:59-67. [PMID: 24565312 PMCID: PMC4453498 DOI: 10.15288/jsads.2014.s17.59] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 07/22/2013] [Indexed: 07/03/2024] Open
Abstract
OBJECTIVE This article reviews developments in research on genetic influences on alcohol and other drug use and disorders over the past 7 decades. METHOD The author began with a review of the flow and content of articles published in the three iterations of the journal since 1940 and then used a PubMed search of genetics of alcohol and other drug-related topics to gain a broad overview of developments in this field. RESULTS The literature demonstrates the rapid metamorphosis of genetic research from the ideas of Mendel to an understanding that the substance use disorders are complex, genetically influenced conditions where genes explain up to 60% of the picture. Most genes operate through additional intermediate characteristics, such as impulsivity and a low sensitivity to alcohol, some of which are substance specific and others related to substances in general. Using linkage, association, genome-wide association, and other modern methods, investigators have identified a diverse range of genetic variations that affect substance-related phenomena. CONCLUSIONS Genetic studies regarding alcohol and other drug use and problems have grown dramatically in the past 75 years. We currently have a much more sophisticated understanding of these influences, and the rapid development of new methods has the promise of continuing what has been a solid contribution of important findings in recent years.
Collapse
Affiliation(s)
- Marc A. Schuckit
- Department of Psychiatry, University of California,
San Diego, La Jolla, California
| |
Collapse
|
|
34
|
Spanagel R. Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks. In Silico Pharmacol 2013; 1:18. [PMID: 25505662 PMCID: PMC4230431 DOI: 10.1186/2193-9616-1-18] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 11/12/2013] [Indexed: 01/16/2023] Open
Abstract
Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. "from phenotype to genotype". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. "from genotype to phenotype". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior.
Collapse
Affiliation(s)
- Rainer Spanagel
- Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| |
Collapse
|
|
35
|
Roman S, Zepeda-Carrillo EA, Moreno-Luna LE, Panduro A. Alcoholism and liver disease in Mexico: genetic and environmental factors. World J Gastroenterol 2013; 19:7972-7982. [PMID: 24307790 PMCID: PMC3848144 DOI: 10.3748/wjg.v19.i44.7972] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 08/15/2013] [Accepted: 10/17/2013] [Indexed: 02/06/2023] Open
Abstract
Alcoholism and cirrhosis, which are two of the most serious health problems worldwide, have a broad spectrum of clinical outcomes. Both diseases are influenced by genetic susceptibility and cultural traits that differ globally but are specific for each population. In contrast to other regions around the world, Mexicans present the highest drinking score and a high mortality rate for alcoholic liver disease with an intermediate category level of per capita alcohol consumption. Mexico has a unique history of alcohol consumption that is linked to profound anthropological and social aspects. The Mexican population has an admixture genome inherited from different races, Caucasian, Amerindian and African, with a heterogeneous distribution within the country. Thus, genes related to alcohol addiction, such as dopamine receptor D2 in the brain, or liver alcohol-metabolizing enzymes, such as alcohol dehydrogenase class I polypeptide B, cytochrome P450 2E1 and aldehyde dehydrogenase class 2, may vary from one individual to another. Furthermore, they may be inherited as risk or non-risk haplogroups that confer susceptibility or resistance either to alcohol addiction or abusive alcohol consumption and possibly liver disease. Thus, in this era of genomics, personalized medicine will benefit patients if it is directed according to individual or population-based data. Additional association studies will be required to establish novel strategies for the prevention, care and treatment of liver disease in Mexico and worldwide.
Collapse
|
|
36
|
Spanagel R, Durstewitz D, Hansson A, Heinz A, Kiefer F, Köhr G, Matthäus F, Nöthen MM, Noori HR, Obermayer K, Rietschel M, Schloss P, Scholz H, Schumann G, Smolka M, Sommer W, Vengeliene V, Walter H, Wurst W, Zimmermann US, Stringer S, Smits Y, Derks EM. A systems medicine research approach for studying alcohol addiction. Addict Biol 2013; 18:883-96. [PMID: 24283978 DOI: 10.1111/adb.12109] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
According to the World Health Organization, about 2 billion people drink alcohol. Excessive alcohol consumption can result in alcohol addiction, which is one of the most prevalent neuropsychiatric diseases afflicting our society today. Prevention and intervention of alcohol binging in adolescents and treatment of alcoholism are major unmet challenges affecting our health-care system and society alike. Our newly formed German SysMedAlcoholism consortium is using a new systems medicine approach and intends (1) to define individual neurobehavioral risk profiles in adolescents that are predictive of alcohol use disorders later in life and (2) to identify new pharmacological targets and molecules for the treatment of alcoholism. To achieve these goals, we will use omics-information from epigenomics, genetics transcriptomics, neurodynamics, global neurochemical connectomes and neuroimaging (IMAGEN; Schumann et al. ) to feed mathematical prediction modules provided by two Bernstein Centers for Computational Neurosciences (Berlin and Heidelberg/Mannheim), the results of which will subsequently be functionally validated in independent clinical samples and appropriate animal models. This approach will lead to new early intervention strategies and identify innovative molecules for relapse prevention that will be tested in experimental human studies. This research program will ultimately help in consolidating addiction research clusters in Germany that can effectively conduct large clinical trials, implement early intervention strategies and impact political and healthcare decision makers.
Collapse
Affiliation(s)
- Rainer Spanagel
- Insitute of Psychopharmacology; Central Institute of Mental Health; Medical Faculty Mannheim; University of Heidelberg; Germany
| | - Daniel Durstewitz
- Bernstein Center for Computational Neuroscience; Central Institute of Mental Health; Germany
| | - Anita Hansson
- Insitute of Psychopharmacology; Central Institute of Mental Health; Medical Faculty Mannheim; University of Heidelberg; Germany
| | - Andreas Heinz
- Department of Addictive Behaviour and Addiction Medicine; Central Institute of Mental Health; Germany
| | - Falk Kiefer
- Department of Genetic Epidemiology in Psychiatry; Central Institute of Mental Health; Germany
| | - Georg Köhr
- Insitute of Psychopharmacology; Central Institute of Mental Health; Medical Faculty Mannheim; University of Heidelberg; Germany
| | | | - Markus M. Nöthen
- Department of Psychiatry; Charité University Medical Center; Germany
| | - Hamid R. Noori
- Insitute of Psychopharmacology; Central Institute of Mental Health; Medical Faculty Mannheim; University of Heidelberg; Germany
| | - Klaus Obermayer
- Institute of Applied Mathematics; University of Heidelberg; Germany
| | - Marcella Rietschel
- Department of Genomics, Life & Brain Centre; University of Bonn; Germany
| | - Patrick Schloss
- Neural Information Processing Group; Technical University of Berlin; Germany
| | - Henrike Scholz
- Behavioral Neurogenetics' Zoological Institute; University of Cologne; Germany
| | - Gunter Schumann
- MRC-SGDP Centre; Institute of Psychiatry; King's College; UK
| | - Michael Smolka
- Department of Psychiatry and Psychotherapy; Technical University Dresden; Germany
| | - Wolfgang Sommer
- Insitute of Psychopharmacology; Central Institute of Mental Health; Medical Faculty Mannheim; University of Heidelberg; Germany
| | - Valentina Vengeliene
- Insitute of Psychopharmacology; Central Institute of Mental Health; Medical Faculty Mannheim; University of Heidelberg; Germany
| | - Henrik Walter
- Department of Addictive Behaviour and Addiction Medicine; Central Institute of Mental Health; Germany
| | - Wolfgang Wurst
- Institute of Developmental Genetics; Helmholtz Center Munich; Germany
| | - Uli S. Zimmermann
- Department of Psychiatry and Psychotherapy; Technical University Dresden; Germany
| | - Sven Stringer
- Psychiatry Department; Academic Medical Center; The Netherlands
- Brain Center Rudolf Magnus; University Medical Center; The Netherlands
| | - Yannick Smits
- Psychiatry Department; Academic Medical Center; The Netherlands
| | - Eske M. Derks
- Psychiatry Department; Academic Medical Center; The Netherlands
| | | |
Collapse
|
|
37
|
Nieratschker V, Batra A, Fallgatter AJ. Genetics and epigenetics of alcohol dependence. J Mol Psychiatry 2013; 1:11. [PMID: 25408904 PMCID: PMC4223883 DOI: 10.1186/2049-9256-1-11] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 07/03/2013] [Indexed: 11/22/2022] Open
Abstract
Alcohol dependence is a severe and common disorder associated with high morbidity and mortality rates. Genetic as well as environmental factors are known to modulate susceptibility to alcohol dependence. There is a growing body of evidence suggesting that this interaction between the genome and the environment is mediated by epigenetic mechanisms, e.g. DNA methylation at CpG sites. Following an introduction of epigenetic regulation of gene transcription, this review will provide an overview over recent genetic and epigenetic findings in the context of alcohol dependence focusing on human studies. Finally, we will discuss the current limitations of epigenetic studies as well as the implications of genetic and epigenetic findings for the development of better treatment and prevention strategies.
Collapse
Affiliation(s)
- Vanessa Nieratschker
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Germany, Calwerstrasse 14, Tuebingen, 72076 Germany
| | - Anil Batra
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Germany, Calwerstrasse 14, Tuebingen, 72076 Germany
| | - Andreas J Fallgatter
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Germany, Calwerstrasse 14, Tuebingen, 72076 Germany
| |
Collapse
|
|
38
|
Kos MZ, Yan J, Dick DM, Agrawal A, Bucholz KK, Rice JP, Johnson EO, Schuckit M, Kuperman S, Kramer J, Goate AM, Tischfield JA, Foroud T, Nurnberger J, Hesselbrock V, Porjesz B, Bierut LJ, Edenberg HJ, Almasy L. Common biological networks underlie genetic risk for alcoholism in African- and European-American populations. GENES, BRAIN, AND BEHAVIOR 2013; 12:532-42. [PMID: 23607416 PMCID: PMC3709451 DOI: 10.1111/gbb.12043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 01/22/2013] [Accepted: 04/17/2013] [Indexed: 12/19/2022]
Abstract
Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs). Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P = 1.64 × 10(-3) and 2.08 × 10(-4) for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population specific. Simulations show that disease models based on rare and uncommon causal variants (MAF < 0.05) best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.
Collapse
Affiliation(s)
- M Z Kos
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|