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In this Section
- Major Initiatives
- Medications Development Program
- Underage Drinking Research Initiative
- National Consortium on Alcohol and Neurodevelopment in Adolescence
- Fetal Alcohol Spectrum Disorders
- Collaborative Studies on Genetics of Alcoholism (COGA) Study
- NIAAA-Funded Research Centers
- NIAAA Institutional Research Training Programs
- Other Key Extramural Research Activites
- Guidelines & Resources
- Intramural Research Program
- NIAAA Laboratories
- Laboratory of Behavioral & Genomic Neuroscience
- Laboratory of Clinical & Translational Studies
- LCTS - Office of the Chief
- LCTS - Section on Brain Electrophysiology and Imaging (BEI)
- LCTS - Section of Clinical Assessment and Treatment Evaluation (CATE)
- LCTS - Section on Clinical Psycho-neuroendocrinology and Neuro-psychopharmacology (CPN)
- LCTS - Section on Human Psychopharmacology (HP)
- LCTS - Section of Molecular Pathophysiology (MP)
- Laboratory of Epidemiology and Biometry
- Laboratory for Integrative Neuroscience
- LIN - Office of the Chief
- LIN - Section on Neuronal Structure
- LIN - Section of Synaptic Pharmacology (SP)
- Laboratory of Liver Diseases
- Laboratory of Membrane Biochemistry and Biophysics
- Laboratory of Metabolic Control
- Laboratory of Molecular Physiology
- Laboratory of Molecular Signaling
- Laboratory of Neurogenetics
- Laboratory for Neuroimaging
- Laboratory of Physiologic Studies
- Chemical Biology Research Branch (joint lab with NIDA)
- Office of the Scientific Director
- Office of Laboratory Animal Science (OLAS)
- Research and Training
- Clinical Trials at NIAAA/NIH
- NIAAA Laboratories
LNG - Section of Human Neurogenetics (HN)
David Goldman MD., Section Chief
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5625 Fishers Lane, Room 3S-32:MSC 9412
Bethesda MD 20892-9412
telephone: +1 301.443.0059
fax: +1 301.480.2839
Serves as the Section Chief of Human Neurogenetics, NIAAA
Human Neurogenetics, directed by David Goldman, MD, identifies functional loci that modulate pathways to vulnerability to alcoholism, other addictions, and related psychiatric disorders. To accomplish this it generates clinical datasets and collaborates with multiple laboratories. Its activities encompass human research protocols, large scale SNP detection using massively parallel sequencing, array and capillary electrophoresis based genotyping, in vitro and in vivo functional analyses of receptor variants, linkage studies of markers and candidate alleles, genome linkage scans, genome-wide associations, genome-wide epigenetic analyses, transcriptome analyses, and genome informatics.
The major paradigm of LNG is the study of inter-individual variation and its relation to behavior. The aim is to relate genotype to complex behavioral phenotypes, with the goal of identifying vulnerability and protective alleles responsible for the substantial heritability of alcoholism. To accomplish this, LNG studies intermediate phenotypes which assay functions of neurobiological systems integral to alcoholism and other addictions. These mechanisms include anxiety/stress response, executive cognitive function and behavioral control, and reward. Identification of alleles influencing these mechanisms will lead to better understanding of vulnerability, gene-environment interactions, molecular diagnostic markers to individualize treatment, and molecular targets for intervention.
Mary-Anne Enoch, M.D.,
|Mary-Anne Enoch, M.D., (Staff Scientist) with LNG since 1995, has pursued two major interests: the use of intermediate phenotypes, including electrophysiological phenotypes and dimensional anxiety, for understanding the genetics and neurobiology of alcoholism and co-morbid disorders, and the influence of gene-environment interactions on addiction. The large psychiatric and electrophysiological phenotype datasets Dr. Enoch developed, or for which she led electrophysiology studies, are US Caucasians, Plains Indians, and Southeastern American Indians. She has published papers on the interactions of sex with gene effects, and more recently in the interactive effects of childhood trauma and genetic variation on addictive disorders and associated psychopathology. Recent findings include associations between GABRA2 and GABRG1 haplotypes and alcoholism, additive effects between functional variants in 5-HTTLPR and HTR3B on risk for alcohol and drug dependence, and the association of CRH-BP, identified as a candidate gene through a whole genome linkage scan, with EEG power, alcoholism and anxiety. Dr. Enoch serves on the NIH Neuroscience IRB.|
Colin Hodgkinson, Ph.D.,
Colin Hodgkinson, Ph.D., (Staff Scientist) who joined LNG in 2003 and leads the DNA/Data core. He directs high throughput sequencing and genotyping, genetic linkage, and functional genetic analyses. Using the high-density haplotype approach in a large case-control dataset, Dr. Hodgkinson replicated and extended linkage of DISC1 to schizoaffective disorder, and is exploring the relationship of DISC1 and genes to which it is functionally related in various phenotypes. He recently identified multiple genes influencing the electroencephalogram by genome-wide association.
Kornel Schuebel, Ph.D.
Kornel Schuebel, Ph.D., (Staff Scientist) who joined LNG in 2008 He is intimately involved with all aspects of genome-wide discovery and functionation of DNA methylation, chromatin, and RNA metabolism as it pertains to gene expression alterations in pathological brain disorders, with a focus on fetal alcohol syndrome. Dr. Schuebel directs analyses with the ABI SOLiD, enabling massively parallel sequencing.
Laura Bevilacqua, M.D.,
Laura Bevilacqua, M.D., is a Fogarty fellow appointed 2007. She received her M.D. in 2005 from the University of Pisa where she also has been trained in psychiatry. She is interested in functional genomics, from genome informatics to in vivo and in vitro functional assays. She is focusing on the role of serotonin and dopamine domain genes in impulsivity and dyscontrol towards the identification of functional alleles in addictions and related behaviors. In this respect she is performing next generation sequencing studies on dyscontrol behaviors and plans to extend it to whole genome transcriptomes and microRNAs. She recently detected a stop codon that is common in the Finnish population and that influences impulsivity.
Vibhuti Srivastava, Ph.D.,
Vibhuti Srivastava Ph.D., is a Fogarty fellow from the University of Delhi appointed 2008. She is interested in understanding mechanisms of genome wide epigenetic regulation using cell lines, animal models and human tissues. She uses microarray and next generation sequencing technology for whole genome transcriptome and DNA methylation analyses. She is also focusing on oxidative stress induced brain volume alterations among alcoholics. In this regard, she has found MnSOD2 gene effect on gray matter shrinkage among chronic alcoholics. She is also identifying population specific chromosomal signatures in seemingly admixed populations.
Zhifeng Zhou, Ph.D.,
Zhifeng Zhou, Ph.D., who joined LNG in 2002 is a molecular biologist, works on the new generation of high-throughput sequencing approach to study drug- and alcohol-related genome-wide changes of gene expression and epigenetic regulation. Dr. Zhou also conducted research projects which uncovered multilevel effects of haplotype-based Neuropeptide Y (NPY) gene expression variation on emotion and stress responses and linked haplotype-base genetic association of TPH2 gene with susceptibility of depression and suicide behavior. Recently he has mapped gene expression and epigenetic change in the hippocampus of alcoholics and cocaine addicts.
Qiaoping Yuan, Ph.D.,
Qiaoping Yuan, Ph.D., who joined LNG in 2005 is a bioinformatics and analytical IT tools resource for all members of LNG. He is in the DNA/Data Core where he leads genome informatics including creating analytic frameworks and pathways for the next-gen sequencer data. He is involved in all genomics projects of LNG, both at the front end of designing arrays and planning analyses and at the analytical phases.
Pei-Hong Shen, M.S.,
|Pei-Hong Shen, M.S., who joined LNG in 2004 is involved in all aspects of the data analysis and data management to identify genetic variation, define molecular functionality, and link genetic variation to intermediate phenotypes and complex behavior. She is a bioinformatics and analytical IT tools resource for all members of LNG.|
Chery Marietta, M.S.,
|Cheryl Marietta, M.S., with NIAAA since 1980, a Senior Research Assistant in the lab. She is involved in the Induced Pluripotent Stem Cell (IPSC) project and will be generating neurons from the IPSC’s as well as assisting with various other projects. She is also the Chairperson of the NIAAA Safety Committee.|
Longina Akhtar , M.S.,
|Longina Akhtar, M.S., with LNG since 1983, manages the front-end of multiple collaborations requiring preparation of DNA and/or lymphoblastoid cell lines. She performs or supervises all the primary cell culture, DNA extractions from cells and blood, and cell storage – including off-site backup. She assists in the construction of DNA panels for linkage studies. Her position is broad in scope and responsibility in that she is the direct, and frequent point of interaction with many collaborating investigators.|
Elisa Moore, Sr. Systems Analysis/Specialist and Robotics, has been with LNG since 1993. She performs work in applying analytical processes to the planning, design, and implementation of new/improved information systems with unique requirements in cutting edge scientific research and bioinformatics environment. She designed specialized networks with terabytes of data flow between next-generation sequencers and mass storage arrays, supports specialized computers on DNA sequencers, analyzers and real-time PCR equipment., programs DNA liquid handling robotics and works on other “front-end” aspects of high throughput genetic analysis.
Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, Zhou Z, Wedenoja J, Maroteaux L, Diaz S, Belmer A, Hodgkinson CA, Dell'osso L, Suvisaari J, Coccaro E, Rose RJ, Peltonen L, Virkkunen M, Goldman D. A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 2010; 468: 1061-1066.
This discovery of a population specific stop codon leading to severe impulsivity has implications for several psychiatric diseases and represents the first successful application of deep sequencing for gene discovery in complex diseases.
Enoch M-A, Gorodetsky E, Hodgkinson CA, Roy A, Goldman D. Functional Genetic Variants that Increase Synaptic Serotonin and 5-HT3 Receptor Sensitivity Predict Alcohol and Drug Dependence. Mol Psychiatry 2010 Sep 14. [Epub ahead of print].
This study demonstrates the utility of investigating genetic influences on neurotransmitter pathways for identifying risk for alcohol and drug dependence.
Hodgkinson CA, Enoch M-A, Srivastava V, Cummins-Oman JS, Ferrier C, Iarikova P, Sankararaman S, Yamini G, Yuan Q, Zhou Z, Albaugh B, White KV, Shen P-H, Goldman D. Genome-wide association identifies candidate genes that influence the human electroencephalogram. Proc Natl Acad Sci U S A. 2010; 107: 8695-8700.
This genome wide association study (GWAS) of a heritable intermediate phenotype for alcoholism and other psychiatric diseases detected multiple genome-wide significant loci.
Enoch M-A, Hodgkinson CA, Yuan Q, Shen P-H, Goldman D, Roy A. The Influence of GABRA2, Childhood Trauma and their Interaction on Alcohol, Heroin and Cocaine Dependence. Biol Psychiatry 2010; 67: 20-27.
The results of this study suggest that at least in African-American men, childhood trauma, GABRA2 variation, and their interaction play a role in risk-resilience for substance dependence.
Hong LE, Hodgkinson CA, Yang Y, Sampath H, Ross TJ, Buchholz B, Salmeron BJ, Srivastava V, Thaker GK, Goldman D, Stein EA. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. Proc Natl Acad Sci U S A. 2010; 107: 13509-13514.
This imaging genetic study reveals part of the mechanism of action of CHRNA5 Asn398Asp in nicotine addiction.
Anton RF, Oroszi G, O’Malley S, Couper D, Swift R, Pettinati H, Goldman D: An Evaluation of μ-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence. Arch Gen Psychiatry 2008; 65: 135-144.
This study represents a critical replication of the pharmacogenetic predictive use of a functional OPRM1 missense variant in alcoholics treated with naltrexone.
Enoch M-A, Shen P-H, Ducci F, Yuan Q, Liu J, Albaugh B, White KV, Hodgkinson C, Goldman D. Common Genetic Origins for EEG, Alcoholism and Anxiety: the Role of CRHBP. PLoS ONE, 3(10):e3620. Epub 2008 Oct 31.
This study indicates a likely role for CRHBP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction.
Zhou Z, Zhu G, Hariri A, Enoch M-A, Scott D, Sinha R, Virkkunen M, Mash D, Lipsky R, Hu X-Z, Hodgkinson C, Xu K, Buzas B, Yuan Q, Shen P-H, Ferrell R, Manuck S, Brown S, Hauger R, Stohler C, Zubieta J-K, Goldman D. Genetic variation in human NPY expression affects stress response and emotion. Nature 2008; 452(7190): 997-1001.
In a multilevel analysis of complex behavior, a functional haplotype, and functional loci were identified at the gene for neuropeptide Y, an anxiolytic neuropeptide. There were modest but significant effects of NPY haplotype on complex behavior but much stronger effects in two stress/emotion brain imaging paradigms and on neuropeptide and mRNA expression, including molecular expression in postmortem brain.
Sjöberg RL, Ducci F, Barr CS, Newman TK, Dell'osso L, Virkkunen M, Goldman D.
A non-additive interaction of a functional MAO-A VNTR and testosterone predicts antisocial behavior. Neuropsychopharmacology 2008; 33: 425-430.
In the first gene x endocrine interaction study in psychiatric genetics the low expression MAOA allele was shown to be permissive for the effect of testosterone to increase aggression in males. The impetus for the study is an androgen response element in the MAOA promoter.
Ducci F, Enoch MA, Hodgkinson C, Xu K, Catena M, Robin RW, Goldman D.
Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Mol Psychiatry 2008; 13: 334-347.
In a gene x stress interaction study the low expression MAOA allele interacts with childhood sexual abuse to increase risk for two psychiatric diseases marked by behavioral dyscontrol, namely antisocial personality disorder and alcoholism.
Hu X, Lipsky R, Zhu G, Akhtar L, Taubman J, Greenberg BD, Xu K, Arnold P, Richter M, Kennedy JL, Murphy D, Goldman D. Serotonin Transporter Promoter Gain-of-function Genotypes Are Linked to Obsessive-compulsive Disorder. Am J Hum Genet 2006; 78: 815-826.
A novel, common, functional allele was discovered in psychiatric genetics’ most often studied locus. Function was demonstrated via in vivo and in vitro experiments including decoy DNA for the specific transcription factor whose binding is altered by the SNP.
Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003; 299(5610):1240-1243.
This is one of the first imaging genetics papers, relating a functional polymorphism to variation in human pain and emotional response.
Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 297(5580): 400-403.
This is one of the first imaging genetics papers, relating a functional polymorphism to variation in human emotional response.