Laboratory of Neurogenetics
Overview of the Lab
Human Neurogenetics 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.
1: Kwako LE, Momenan R, Litten RZ, Koob GF, Goldman D. Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders. Biol Psychiatry. 2015 Nov 17. pii: S0006-3223(15)00954-3.
Neuroscience measures of domains important in the “addiction cycle” can enhance clinical science and research.
2: Peciña M, Martínez-Jauand M, Hodgkinson C, Stohler CS, Goldman D, Zubieta JK. FAAH selectively influences placebo effects. Mol Psychiatry. 2014;19: 385-391.
A functional polymorphism of FAAH, which metabolizes the endocannabinoid anandamide, has been linked to alcoholism and other behaviors, and here, in a neuroimaging paradigm to pain/placebo response.
3: Zhou Z, Karlsson C, Liang T, Xiong W, Kimura M, Tapocik JD, Yuan Q, Barbier E, Feng A, Flanigan M, Augier E, Enoch MA, Hodgkinson CA, Shen PH, Lovinger DM, Edenberg HJ, Heilig M, Goldman D. Loss of metabotropic glutamate receptor 2 escalates alcohol consumption. Proc Natl Acad Sci U S A. 2013; 110: 16963-16968. In the artificially selected alcohol preferring (P) rat, a stop codon in the metabotropic glutamate receptor 2 leads to uncompensated loss of function, escalated alcohol consumption, and changes in expression of a network of glutamate genes, pointing to a role for this gene and glutamate function in alcoholism.
4: Yuan Q, Zhou Z, Lindell SG, Higley JD, Ferguson B, Thompson RC, Lopez JF, Suomi SJ, Baghal B, Baker M, Mash DC, Barr CS, Goldman D. The rhesus macaque is three times as diverse but more closely equivalent in damaging coding variation as compared to the human. BMC Genet. 2012; 13:52.
At a genome wide level, humans are less diverse than primates to which we are evolutionarily related, but closer to them in terms of variation that is potentially damaging.
5: Enoch MA, Zhou Z, Kimura M, Mash DC, Yuan Q, Goldman D. GABAergic gene expression in postmortem hippocampus from alcoholics and cocaine addicts; corresponding findings in alcohol-naïve P and NP rats. PLoS One. 2012;7(1):e29369.
This study confirmed the involvement of the GABAergic system in alcohol use disorders but also revealed a hippocampal GABA input in cocaine addiction. Congruent findings in human addicts and P rats provide clues to predisposing factors for alcohol and drug addiction.
6: Bevilacqua L, Carli V, Sarchiapone M, George DK, Goldman D, Roy A, Enoch MA. Interaction between FKBP5 and childhood trauma and risk of aggressive behavior. JAMA Psychiatry. 2012; 69: 62-70.
This was the first study to show that childhood trauma and FKBP5 gene variants interact to increase the risk of overt aggressive behavior.
7: Goldman, D. Our Genes, Our Choices, Elsevier (Academic Press), 2012.
How free will emerges from neurogenetic individuality and self-guided neurodevelopmental plasticity.
8: 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 2011; 16: 1139-1146.
This study demonstrated the utility of investigating genetic influences on neurotransmitter pathways for identifying risk for alcohol and drug dependence.
9: Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch M-A. The Interaction of FKBP5, a Stress Related Gene, with Childhood Trauma Increases the Risk for Attempting Suicide. Neuropsychopharmacology 2010; 35: 1674-1683.
This study has shown that childhood trauma and FKBP5 gene variants interact to increase the risk for suicidal behavior, at least in African American substance dependent treatment-seeking patients.
10: 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.
11: 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.
12: 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.
13: 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.
14: 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.
15: 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.
16: 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.
17: 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.
18: 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.
19: 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.