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. Author manuscript; available in PMC: 2019 Aug 1.
Published in final edited form as: Gene. 2015 Feb 2;560(2):184–194. doi: 10.1016/j.gene.2015.01.064

Clinically relevant genetic biomarkers from the brain in alcoholism with representation on high resolution chromosome ideograms

Ann M Manzardo a,*, Austen McGuire a, Merlin G Butler a,b
PMCID: PMC6675570  NIHMSID: NIHMS1043701  PMID: 25655461

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.

Keywords: High resolution chromosome ideograms, Alcoholism, Genetic biomarkers, Brain, Chromosome band location, Gene

1. Introduction

Alcoholism arises from the combined effects of multiple biological factors including a wide range of possible genetic variations and/or abnormalities, as well as non-genetic causes including interpersonal and psychosocial relationships, neuroadaptive responses, and gene/environmental interaction (epigenetics)( Enoch, 2013; Koob, 2013; Mayfield et al., 2008; Morozova et al., 2014; Rietschel and Treutlein, 2013). The risk to develop alcoholism is strongly related to the family history, childhood environment particularly the number of life stressors and presence or absence of co-occurring mental disorders (Bierut et al., 1998; Brady and Back, 2012; Brady and Sinha, 2005; Enoch, 2013; Keyes et al., 2012; Schepis et al., 2011). The interface of these relationships are complex and involve overlapping and competing effects of many genes impacting brain development, structure, and function, as well as, alcohol processing and sensitivity (Enoch, 2013; Koob, 2013).

1.1. Candidate gene strategies

Alcohol-responsive brain networks have been reported and identified by case–control, population and family-based studies incorporating candidate gene approach with whole-genome methodology in individuals with and without alcoholism (Edenberg, 2012; Edenberg and Foroud, 2006, 2013; Enoch, 2013; Morozova et al., 2014; Yan et al., 2014). Candidate gene strategies have considered neurobiological and neurodevelopmental pathways which are key to brain function by emphasizing emotion and reward pathways as well as biochemical processes associated with the physiologic effects and molecular targets of alcohol itself particularly those impacting alcohol metabolism (Blum et al., 1990; Bolos et al., 1990; Chai et al., 2005; Edenberg et al., 2006, 2008; Enoch, 2013; Feinn et al., 2005; Kapoor et al., 2014; Luo et al., 2005; Macgregor et al., 2009; Radel et al., 2005; Tolstrup et al., 2008; Wetherill et al., 2014; Zhang et al., 2008). Further, genetic biomarkers including chromosome regions have been identified by overlapping genetic linkage and functional data with alcoholism-related phenotypes of interest and refined to develop a molecular signature of alcoholism phenotype (Ehlers et al., 2004; Enoch, 2013; Kapoor et al., 2014; Wetherill et al., 2014). A representative example of a candidate gene/biomarker analysis is the alcohol dehydrogenase enzyme (ADH) which is responsible for alcohol metabolism and linked to the ADH gene family located in the 4q23 chromosome band (Chai et al., 2005; Edenberg et al., 2006; Macgregor et al., 2009; Tolstrup et al., 2008). The 4q23 chromosome band has been strongly associated with alcoholism vulnerability in several genome-wide linkage studies (Long et al., 1998; Reich et al., 1998). The activity of alcohol metabolizing enzymes (e.g., ADH) influences sensitivity to alcohol, its effects on the body and the accumulation of metabolites (e.g., acetaldehyde) which may be toxic. Genetic variants that increase production or slow the processing of alcohol intermediates (e.g., ADH1B, ADH1C, ALDH2) influence the likelihood of developing a drinking problem (Chai et al., 2005; Edenberg et al., 2006; Macgregor et al., 2009; Tolstrup et al., 2008). Human genetic studies have similarly identified alcoholism candidate genes involving neurotransmitter pathways associated with brain reward processes including the dopaminergic (e.g., DRD2, MAOA, COMT), serotoninergic (e.g., HTR3A, HTR1B, HTR3B), GABAergic (e.g., GABRA1, GABRA2), glutaminergic (GAD1, GRIK3, GRIN2C) and opioid (e.g., OPRM1, OPRD1; Blum et al., 1990; Bolos et al., 1990; Edenberg, 2012; Edenberg and Foroud, 2013; Edenberg et al., 2008; Feinn et al., 2005; Luo et al., 2005; Radel et al., 2005; Zhang et al., 2008). These genes presumably directly impact the reinforcing properties of alcohol driving the motivation to seek and use alcohol to excess. Whole-genome studies have shown abnormalities of chromosomes and identified specific regions (e.g., 4p12, 7q31.32, 13q14.2) where known or candidate genes for alcoholism are located and for alcoholism-related phenotypes such as age of drinking onset (3q26.1, 5q11.2, and 12q32.2; Edenberg, 2012; Edenberg and Foroud, 2013; Enoch, 2013; Kapoor et al., 2014; Morozova et al., 2014; Radel et al., 2005; Yan et al., 2014).

1.2. Whole genome investigation

Advances in genetic technology beyond linkage or cytogenetic analysis of affected families with alcoholism or other complex disorders using COGA, SAGE, and other resources have led to genome-wide association studies (GWAS) involving hundreds of affected and control individuals analyzing the distribution and clustering of hundreds and thousands of SNPs to search for candidate genes (Edenberg, 2012; Edenberg and Foroud, 2013; Enoch, 2013; Morozova et al., 2014; Rietschel and Treutlein, 2013; Yan et al., 2014). GWAS studies have identified genetic linkage to primary disease risk, alcoholism-related phenotypes and responsiveness such as consumption, level of response to alcohol’s effects and event-related potential. Examples of candidate genes identified by GWAS studies include functional roles in cell adhesion important for brain development and implicated in Autism Spectrum Disorder (e.g., AUTS2, CDH13, EFNA5), molecular transporters (e.g., SLC1A3, SLC5A11, SLC6A4), and growth factors (e.g., BDNF) (Edenberg, 2012; Edenberg and Foroud, 2006, 2013; Enoch, 2013; Morozova et al., 2014; Rietschel and Treutlein, 2013; Yan et al., 2014).

1.3. Functional genomic biomarkers from brain

Additional functional genomic biomarker studies using high resolution microarrays have identified regionally distinct gene and exon level expression disturbances in post-mortem brain impacting neuronal growth and function which may influence alcoholism onset and progression (Flatscher-Bader et al., 2005, 2006, 2010; Lewohl et al., 2000; Liu et al., 2004, 2006; Manzardo et al., 2014; Mayfield et al., 2002; Sokolov et al., 2003). Functional gene expression profiling has identified disturbances in selected brain regions associated with reward processing and prefrontal inhibitory control mechanisms relevant to the development and propagation of abuse behaviors (Flatscher-Bader et al., 2005, 2006, 2010; Lewohl et al., 2000; Liu et al., 2004, 2006; Manzardo et al., 2014; Mayfield et al., 2002; Sokolov et al., 2003). An overrepresentation of down-regulated vs up-regulated genes at the mRNA level have been reported in addiction-related brain regions and functional disturbances impacting myelination, cellular signaling and energy production influencing brain structure, function, growth and development (Lewohl et al., 2000; Liu et al., 2004, 2006; Manzardo et al., 2014; Mayfield et al., 2002; Sokolov et al., 2003). These effects have been correlated with medical and psychiatric co-morbidities such as cirrhotic liver disease, smoking status and/or nutritional deficiency (Liu et al., 2007) and become potential genetic biomarkers for considerations in assessment and treatment development.

Advanced genetic platforms incorporating sophisticated bioinformatics techniques have enhanced our ability to identify SNPs and bio-markers involved in the genetics of alcoholism including risk factors for the development and progression of illness and have provided invaluable insight into the molecular and cellular mechanisms underlying the pathophysiology of alcoholism and the addictions. This insight has contributed to the development of the first targeted, clinically-validated and FDA approved drug treatments for alcoholism. The field will continue to advance through the use of next generation sequencing (whole genome or exome) which will yield additional valuable information on the location and description of genes contributing to alcoholism, enabling the identification of specific and recurring mutations of single genes impacting upon alcoholism-related phenotypes such as tolerance, withdrawal sensitivity, and craving which may provide novel therapeutic targets for future interventions. A current list of clinically relevant genetic biomarkers from brain in alcoholism are summarized and incorporated into high resolution chromosome ideograms (850 band level) to facilitate research, diagnostic testing and genetic counseling options for families in the clinical setting. The location of the 337 genes now recognized by searching literature and website information as playing a role in alcoholism are also presented in tabular form listing the individual gene symbol, name and chromosome location.

2. Materials and methods

We searched key words such as genetics, genes, alcoholism, alcohol abuse and alcohol dependence, mutations or gene variants and gene expression related to molecular disturbances in humans and alcoholism using computer-based internet sources including peer-reviewed medical literature (e.g., PubMed), federally sponsored (e.g., National Center for Biotechnology Information) and other informative websites (e.g., Online Mendelian Inheritance in Man; Ethanol-Related Gene Resource) (Guo et al., 2009) to compile a list of genetic biomarkers. The research articles ascertained were examined for evidence of gene or genetic biomarker involvement in alcoholism causation or pathology. These searches included whole-genome microarray and sequencing data and results from genome-wide association studies (GWAS) of alcoholism and families with and without a history of alcoholism as well as functional gene expression profiles using human brain. This list included a total of 337 genes identified with at least one mechanism related to alcoholism, or that could contribute to behavioral or neurological disturbances seen in alcoholism although not necessarily implicated in disease risk or causality (Table 1). The genetic biomarkers recognized, to date, as playing a role in alcoholism susceptibility or causation generally appear to impact alcohol metabolism and major neuro-transmitter pathways related to brain reward such as dopamine, serotonin, GABA, glutamate and opiate receptors and their metabolic pathways. Additional influences are noted for neurodevelopmental, molecular transport and cellular signaling pathways associated with alcohol exposure and pathophysiology and functionally disturbed in brain expression studies with possible impact on disease course. We include gene symbols representing each biomarker, their expanded name and chromosome band location in Table 1 for the 337 separate genes with a possible role in alcoholism. The position for each gene is plotted on high resolution chromosome ideograms (850 band level) as shown in Figure 1.

Table 1.

Genetic biomarkers for alcoholism and alcohol-responsiveness in human brain.

Gene symbol Gene name Location References
AADAC Arylacetamide deacetylase 3q25.1 Flatscher-Bader et al. (2005)
ABCA1 ATP-binding cassette, subfamily A, member 1 9q31.1 Liu et al. (2007)
ABCA8 ATP-binding cassette, subfamily A, member 8 17q24.2 Manzardo et al. (2014)
ACACB Acetyl-CoA carboxylase-beta 12q24.11 Manzardo et al. (2014)
ACN9 ACN9, S. cerevisiae, homolog of 7q21.3 Dick et al. (2008)
ACO1 Aconitase 1, soluble 9p21.1 Flatscher-Bader et al. (2005)
ACOT12 Acyl-CoA thioesterase 12 5q14.1 Flatscher-Bader et al. (2005)
ACTG1 Actin, gamma-1 17q25.3 Hill et al. (2004)
ACTN4 Actinin, alpha-4 19q13.2 Joslyn et al. (2010); Yu et al. (2008)
ADH1A Alcohol dehydrogenase 1A, class I, alpha polypeptide 4q23 Morozova et al. (2014)
ADH1B Alcohol dehydrogenase 1B, class I, beta polypeptide 4q23 Edenberg (2007)
ADH1C Alcohol dehydrogenase 1C, class I, gamma polypeptide 4q23 Rietschel and Treutlein (2013)
ADH4 Alcohol dehydrogenase 4 4q23 Zuo et al. (2011)
ADH5 Alcohol dehydrogenase 5, chi polypeptide 4q23 Zuo et al. (2011)
ADH6 Alcohol dehydrogenase 6 4q23 Flatscher-Bader et al. (2005)
ADO 2-aminoethanethiol dioxygenase 10q21.3 Guo et al. (2009)
AGT Angiotensinogen 1q42.2 Liu et al. (2006)
ALDH1A1 Aldehyde dehydrogenase 1 family, member A1 9q21.13 Morozova et al. (2014)
ALDH1B1 Aldehyde dehydrogenase 1 family, member B1 9p13.2 Linneberg et al. (2010)
ALDH2 Aldehyde dehydrogenase 2 family 12q24.12 Cui et al. (2009)
ALDOC Aldolase C, fructose-bisphosphate 17q11.2 Guo et al. (2009)
ALK Anaplastic lymphoma kinase 2p23.2-p23.1 Wang et al. (2011b)
AMPH Amphiphysin 7p14.1 Flatscher-Bader et al. (2005)
ANKK1 Ankyrin repeat and kinase domain containing 1 11q23.2 Yang et al. (2008)
ANKRD7 Ankyrin repeat domain 7 7q31.31 Chen et al. (2012)
ANKS1A Ankyrin repeat and sterile alpha motif domain containing 1A 6p21.31 Heath et al. (2011)
ANLN Anillin, actin binding protein 7p14.2 Manzardo et al. (2014)
ANP32E Acidic leucine-rich nuclear phosphoprotein 32 family, member E 1q21.2 Liu et al. (2006)
APOA1 Apolipoprotein A-I 11q23.3 Mayfield et al. (2002)
APOD Apolipoprotein D 3q29 Mayfield et al. (2002)
APP Amyloid beta A4 precursor protein 21q21.3 Flatscher-Bader et al. (2005)
AQP4 Aquaporin 4 18q11.2 Liu et al. (2007)
ARF1 ADP-ribosylation factor 1 1q42.13 Liu et al. (2004)
ARF4 ADP-ribosylation factor 4 3p14.3 Liu et al. (2004)
ARID5A AT rich interaction domain-containing protein 5A (MRF1-like) 2q11.2 Zlojutro et al. (2010)
ARIH1 Ariadne, Drosophila, homolog of, 1 15q24.1 Morozova et al. (2014)
ARHGAP11A RHO (rhodopsin) GTPase-activating protein 11A 15q13.3 Morozova et al. (2012)
ARHGAP28 RHO (rhodopsin) GTPase-activating protein 28 18p11.31 Morozova et al. (2012)
ARL2 ADP-ribosylation factor-like 2 11q13.1 Liu et al. (2004)
ARL4D ADP-ribosylation factor-like 4D 17q21.31 Liu et al. (2004)
ARL15 ADP-ribosylation factor-like 15 5q11.2 Kapoor et al. (2014)
ART3 ADP-ribosyltransferase 3 4q21.1 Mayfield et al. (2002)
ASPA Aspartoacylase 17p13.2 Manzardo et al. (2014)
ATP5A1 ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 18q21.1 Guo et al. (2009)
ATP6V1B2 ATPase, H+ transporting, lysosomal 56/58 kDa, V1 subunit B2 8p21.3 Guo et al. (2009)
ATXN1 Ataxin 1 6p22.3 Mayfield et al. (2002)
AUTS2 Autism susceptibility 2 7q11.22 Schumann et al. (2011)
BBX Bobby sox homolog (Drosophila) 3q13.12 Edenberg et al. (2010)
BDNF Brain-derived neurotrophic factor 11p14.1 Zhao et al. (2012)
BNIP3 BCL2/adenovirus E1B 19 kDa interacting protein 3 10q26.3 Flatscher-Bader et al. (2005)
C15ORF32 Chromosome 15 open reading frame 32 15q26.1 Heath et al. (2011)
C4BPB Complement component 4-binding protein, beta chain 1q32.2 Liu et al. (2006)
CA2 Carbonic Anhydrase II 8q21.2 Flatscher-Bader et al. (2005)
CACNG1 Calcium channel, voltage-dependent, gamma-1 subunit 17q24.2 Mayfield et al. (2002)
CALM2 Calmodulin 2 2p21 Mayfield et al. (2002)
CANX Calnexin 5q35.3 Liu et al. (2006)
CAPN3 Calpain 3 15q15.1 Liu et al. (2006)
CAST Calpastatin 5q15 Morozova et al. (2014)
CAT Catalase 11p13 Lind et al. (2012)
CCR1 Chemokine (C–C motif) receptor 1 3p21.31 Mayfield et al. (2002)
CCT3 Chaperonin containing TCP1 (T-complex 1), subunit 3 1q22 Guo et al. (2009)
CD33 CD33 Antigen 19q13.41 Flatscher-Bader et al. (2005)
CDC14A Cell division cycle 14, S. Cerevisiae, homolog A 1p21.2 Flatscher-Bader et al. (2005)
CDKL5 Cyclin-dependent kinase-like 5 Xp22.13 Liu et al. (2006)()
CDH13 Cadherin 13 16q23.3 Rietschel and Treutlein (2013)
CDHR2 Cadherin-related family member 2 5q35.2 Wetherill et al. (2014)
CEBPG CCAAT/enhancer binding protein (C/EBP), gamma 19q13.11 Flatscher-Bader et al. (2005)
CHRM2 Cholinergic receptor, muscarinic, 2 7q33 Luo et al. (2005)
CHRNA3 Cholinergic receptor, neuronal nicotinic, alpha polypeptide 3 15q25.1 Zuo et al. (2011)
CHRNA5 Cholinergic receptor, neuronal nicotinic, alpha polypeptide 5 15q25.1 Wang et al. (2009)
CHRNB2 Cholinergic receptor, neuronal nicotinic, beta polypeptide 2 1q21.3 Ehringer et al. (2007)
CKB Creatine kinase, brain type 14q32.32 Hill et al. (2004)
CLCN4 Chloride channel 4 Xp22.2 Flatscher-Bader et al. (2005)
CLDN11 Claudin 11 3q26.2 Liu et al. (2004); Manzardo et al. (2014)
CNP Cyclic nucleotide phosphodiesterase 17q21.2 Liu et al. (2006)
COMT Catechol-O-methyltransferase 22q11.21 Yang et al. (2008)
COPB2 Coatomer protein complex, subunit beta-2 3q23 Morozova et al. (2014)
CPE Carboxypeptidase E 4q32.3 Mayfield et al. (2002)
CREM cAMP responsive element modulator 10p11.21 Mayfield et al. (2002)
CRMP1 Collapsin response mediator protein 1 4p16.2 Guo et al. (2009)
CRYAA Crystallin, alpha-A 21q22.3 Mayfield et al. (2002)
CRYAB Crystallin, alpha-B 11q23.1 Mayfield et al. (2002)
CSMD1 CUB (complement C1r/C1s, Uegf, Bmp1) and sushi multiple domains 1 8p23.2 Morozova et al. (2012)
CSMD2 CUB and sushi multiple domains 2 1p34.3 Morozova et al. (2012)
CTNNA3 Catenin, alpha-3 10q21.3 Manzardo et al. (2014)
CTNND2 Catenin, delta-2 5p15.2 Morozova et al. (2012)
CXCL12 Chemokine (C-X-C motif) ligand 12 10q11.21 Flatscher-Bader et al. (2005)
CYP2E1 Cytochrome p450, subfamily IIE 10q26.3 Lind et al. (2012)
DDC Dopa decarboxylase 7p12.1 Pan et al. (2013)
DKK2 Dickkopf WNT signaling pathway inhibitor 2 4q25 Kalsi et al. (2010)
DLG2 Discs large, Drosophila, homolog of, 2 11q14.1 Morozova et al. (2014)
DPYSL2 Dihydropyrimidinase-like 2 8p21.2 Taylor and Wang (2014)
DRD2 Dopamine receptor D2 11q23.2 Yang et al. (2008)
DSCAML1 Down syndrome cell adhesion molecule-like 1 11q23.3 Wang et al. (2011a)
DTWD2 DTW domain containing 2 5q23.1 Pan et al. (2013)
EDIL3 EGF (epidermal growth factor)-like repeats and discoidin I-like domains 3 5q14.3 Liu et al. (2006)
EDNRB Endothelin receptor, type B 13q22.3 Wang et al. (2011a)
EEF1G Eukaryotic translation elongation factor 1, gamma 11q12.3 Sokolov et al. (2003)
EFNA5 Ephrin-A5 5q21.3 Wang et al. (2012)
ENO1 Enolase 1 1p36.23 Guo et al. (2009)
ENO3 Enolase 3 17p13.2 Lind et al. (2012)
ENPP2 Ectonucleotide pyrophosphatase/phosphodiesterase 2 8q24.12 Liu et al. (2004); Manzardo et al. (2014)
ETFA Electron-transfer-flavoprotein, alpha polypeptide 15q24.3 Flatscher-Bader et al. (2005)
ETNPPL Ethanolamine-phosphate phospho-lyase 4q25 Manzardo et al. (2014)
EVI2A Ectropic viral integration site 2A 17q11.2 Manzardo et al. (2014)
FGFR2 Fibroblast growth factor receptor 2 10q26.13 Flatscher-Bader et al. (2010)
FH Fumarate hydratase 1q43 Guo et al. (2009)
FN1 Fibronectin 1 2q35 Liu et al. (2004)
FSIP2 Fibrous sheath interacting protein 2 2q32.1 Wang et al. (2012)
FZD9 Frizzled class receptor 9 7q11.23 Mayfield et al. (2002)
GABBR1 GABA (gamma-aminobutyric acid) B receptor 1 6p21.31 Flatscher-Bader et al. (2005)
GABRA1 GABA (gamma-aminobutyric acid) receptor, alpha-1 5q34 Enoch (2008)
GABRA2 GABA (gamma-aminobutyric acid) receptor, alpha-2 4p12 Agrawal et al. (2006)
GABRB1 GABA (gamma-aminobutyric acid) receptor, beta-1 4p12 Liu et al. (2006)
GABRG1 GABA (gamma-aminobutyric acid) receptor, gamma-1 4p12 Enoch (2008)
GABRG2 GABA (gamma-aminobutyric acid) receptor, gamma-2 5q34 Zuo et al. (2011)
GABRG3 GABA (gamma-aminobutyric acid) receptor, gamma-3 15q12 Edenberg (2012)
GAD1 Glutamate decarboxylase 1 2q31.1 Zuo et al. (2011)
GATA4 GATA binding protein 8p23.1 Rietschel and Treutlein (2013)
GFAP Glial fibrillary acidic protein 17q21.31 Liu et al. (2004)
GJB6 Gap junction protein, beta-6 13q12.11 Manzardo et al. (2014)
GKN1 Gastrokine 1 2p13.3 Flatscher-Bader et al. (2005)
GLDN Gliomedin 15q21.2 Manzardo et al. (2014)
GLUD1 Glutamate dehydrogenase 1 10q23.2 Joslyn et al. (2010)
GOSR1 Golgi SNAP (NSF attachment protein) receptor complex member 1 17q11.2 Mayfield et al. (2002)
GOT1 Glutamate oxaloacetate transaminase, soluble 10q24.2 Lind et al. (2012)
GPM6B Glycoprotein M6B Xp22.2 Mayfield et al. (2002)
GRB2 Growth factor receptor-bound protein 2 17q25.1 Guo et al. (2009)
GRIA1 Glutamate receptor, ionotropic, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) 1 5q33.2 Mayfield et al. (2013)
GRIA4 Glutamate receptor, ionotropic, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) 4 11q22.3 Mayfield et al. (2013)
GRIK3 Glutamate receptor, ionotropic, kainate 3 1p34.3 Zuo et al. (2011)
GRIN1 Glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 1 9q34.3 Mayfield et al. (2013)
GRIN2B Glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2B 12p13.1 Mayfield et al. (2013)
GRIN2C Glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2C 17q25.1 Zuo et al. (2011)
GRM8 Glutamate receptor, metabotropic, 8 7q31.33 Chen et al. (2009)
GSN Gelsolin 9q33.2 Kuo et al. (2006)
HIP1 Huntingtin-interacting protein 1 7q11.23 Heath et al. (2011)
HLA-DRA Major histocompatibility complex, class II, DR alpha 6p21.32 Flatscher-Bader et al. (2005)
HLA-DRB1 Major histocompatibility complex, class II, DR beta 1 6p21.32 Flatscher-Bader et al. (2005)
HLA-DRB4 Major histocompatibility complex, class II, DR beta 4 6p21.3 Flatscher-Bader et al. (2005)
HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase 5q13.3 Mayfield et al. (2002)
HMOX1 Heme oxygenase (decycling) 1 22q13.1 Mayfield et al. (2002)
HSP90B1 Heat-shock protein, 90-kDa, beta, 1 12q23.3 Guo et al. (2009)
HSPA9 Heat-shock 70-kDa protein 9 5q31.2 Guo et al. (2009)
HTR1A 5-hydroxytryptamine receptor 1A 5q12.3 Zuo et al. (2013b)
HTR1B 5-hydroxytryptamine receptor 1B 6q14.1 Cao et al. (2013)
HTR3A 5-hydroxytryptamine receptor 3A 11q23.2 Cao et al. (2013)
HTR3B 5-hydroxytryptamine receptor 3B 11q23.2 Cao et al. (2013)
HTR7 5-hydroxytryptamine receptor 7, adenylate cyclase-coupled 10q23.31 Zlojutro et al. (2010)
IFRD1 Interferon-related developmental regulator 1 7q31.1 Liu et al. (2006)
IGF1 Insulin-like growth factor I 12q23.2 Hill et al. (2004)
IGF1R Insulin-like growth factor 1 receptor 15q26.3 Liu et al. (2004)
IGF2R Insulin-like growth factor II receptor 6q25.3 Morozova et al. (2014)
IKBKB Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta 8q11.21 Flatscher-Bader et al. (2005)
IKZF1 Ikaros family zinc finger 1 7p12.2 Flatscher-Bader et al. (2005)
IL10RA Interleukin 10 receptor, alpha 11q23.3 Mayfield et al. (2002)
IMPA2 Myo-Inositol monophosphatase 2 18p11.21 Morozova et al. (2014)
INADL InaD-like 1p31.3 Heath et al. (2011)
IPO11 Importin 11 5q12.1 Zuo et al. (2013b)
ITGA2 Integrin, alpha-2 5q11.2 Manzardo et al. (2014)
ITGAV Integrin, alpha-V 2q32.1 Flatscher-Bader et al. (2010)
ITPKA Inositol 1,4,5-trisphosphate 3-kinase A 15q15.1 Flatscher-Bader et al. (2005)
KCNB2 Potassium channel, voltage-gated, Shab-related subfamily, member 2 8q13.3 Pan et al. (2013)
KCNE3 Potassium channel, voltage-gated, Isk-related subfamily, member 2 11q13.4 Flatscher-Bader et al. (2005)
KCNIP1 Potassium channel-interacting protein 1 5q31.1 Morozova et al. (2012)
KCNJ6 Potassium channel, inwardly rectifying, subfamily j, member 6 21q22.13 Kang et al. (2012)
KCNJ10 Potassium channel, inwardly rectifying, subfamily j, member 6 11q24.3 Lewohl et al. (2000)
KDM4C Lysine (K)-specific demethylase 4C 9p24.1 Wang et al. (2012)
KIAA0040 Uncharacterized protein 1q25.1 Zuo et al. (2012)
KLK6 Kallikrein-related peptidase 6 19q13.41 Manzardo et al. (2014)
LAMP1 Lysosomal-associated membrane protein 1 13q34 Flatscher-Bader et al. (2005)
LAMP2 Lysosomal-associated membrane protein 2 Xq24 Liu et al. (2006)
LDHB Lactate dehydrogenase B 12p12.1 Guo et al. (2009)
LGR5 Leucine-rich repeat-containing G protein-coupled receptor 5 12q21.1 Manzardo et al. (2014)
LIMS1 LIM and senescent cell antigen-like domains 1 2q12.3 Mayfield et al. (2002)
LMO1 LIM domain only 1 11p15.4 Kapoor et al. (2013)
LPIN1 Lipin 1 2p25.1 Flatscher-Bader et al. (2005)
LPXN Leupaxin 11q12.1 Flatscher-Bader et al. (2005)
LRP2 Low density lipoprotein receptor-related protein 2 2q31.1 Manzardo et al. (2014)
LRRN1 Leucine rich repeats neuronal 1 3p26.2 Wetherill et al. (2014)
LTF Lactotransferrin 3p21.31 Mayfield et al. (2002)
MAG Myelin-associated glycoprotein 19q13.12 Mayfield et al. (2002); Manzardo et al.(2014)
MAOA Monoamine oxidase A Xp11.3 Tikkanen et al. (2009)
MAPT Microtubule-associated protein tau 17q21.31 Flatscher-Bader et al. (2005)
MAX MAX protein 14q23.3 Morozova et al. (2014)
MBP Myelin basic protein 18q23 Liu et al. (2004), Manzardo et al. (2014)
MCM5 Minichromosome maintenance complex component 5 22q13.3 Liu et al. (2006)
MDK Midkine 11p11.2 Flatscher-Bader et al. (2005)
MGST1 Glutathione S-transferase, microsomal, 1 12p12.3 Liu et al. (2007)
MOBP Myelin-associated oligodendrocyte basic protein 3p21.33 Mayfield et al. (2002)
MOG Myelin-oligodendrocyte glycoprotein 6p22.1 Liu et al. (2004); Manzardo et al. (2014)
MPDZ Multiple PDZ (PSD95, Dlg1, & ZO-1) domain protein 9p23 Zhao et al. (2012)
MT1L metallothionein 1 L 16q12.2 Mayfield et al. (2002)
MUS81 MUS81 structure-specific endonuclease subunit 11q13.1 Flatscher-Bader et al. (2005)
MYT1L Myelin transcription factor 1-like 2p25.3 Liu et al. (2004)
NALCN Sodium leak channel, non-selective 13q33.1 Wetherill et al. (2014)
NCAM1 Cell adhesion molecule, neural, 1 11q23.2 Yang et al. (2008)
NDUFA1 NADH (nicotinamide adenine dinucleotide) dehydrogenase (ubiquinone) 1 Xq24 Flatscher-Bader et al. (2005)
NDUFA11 NADH (nicotinamide adenine dinucleotide) dehydrogenase 1 alpha subcomplex, 11 19p13.3 Liu et al. (2006)
NDST4 N-deacetylase/N-sulfotransferase 4 4q26 Pan et al. (2013)
NFKB1 Nuclear factor kappa-B, subunit 1 4q24 Morozova et al. (2014)
NKAIN1 Na+/K+ transporting ATPase interacting 1 1p35.2 Zuo et al. (2013a)
NKAIN2 Na+/K+ transporting ATPase-interacting 2 6q22.31 Wang et al. (2011a)
NPAS3 Neuronal PAS (Per-Arnt-Sim) domain protein 3 14q13.1 Morozova et al. (2012)
NPY Neuropeptide Y 7p15.3 Kauhanen et al. (2000); Mayfield et al. (2002)
NPY1R Neuropeptide Y receptor Y1 4q32.2 Zuo et al. (2011)
NPY2R Neuropeptide Y receptor Y2 4q32.1 Zhao et al. (2012)
NPY5R Neuropeptide Y receptor Y5 4q32.2 Wetherill et al. (2008)
NR4A2 Nuclear receptor subfamily 4, group A, member 2 2q24.1 Pan et al. (2013)
NRD1 Nardilysin 1p32.3 Wang et al. (2011b)
NRXN3 Neurexin 3 14q24.3-q31 Hishimoto et al. (2007)
NSMAF Neutral sphingomyelinase activation-associated factor 8q12.1 Liu et al. (2004)
NTRK2 Neurotrophic tyrosine kinase, receptor, type 2 8q21.33 Mayfield et al. (2002)
OMG Oligodendrocyte-myelin glycoprotein 17q11.2 Hill et al. (2004)
OPRD1 Opioid receptor, delta-1 1p35.3 Ashenhurst et al. (2012); Zhang et al. (2008)
OPRM1 Opioid receptor, mu-1 6q25.2 Ray and Hutchison (2004)
OR51L1 Olfactory receptor, family 51, subfamily L, member 1 11p15.4 Wetherill et al. (2014)
PARK7 Parkinson protein 7 1p36.23 Guo et al. (2009)
PARP1 Poly(ADP-ribose) polymerase 1 1q42.12 Mayfield et al. (2002)
PARP4 Poly(ADP-ribose) polymerase 4 13q12.12 Mayfield et al. (2002)
PDHB pyruvate dehydrogenase, beta polypeptide 3p14.3 Guo et al. (2009)
PDIA3 Protein disulfide isomerase, family A, member 3 15q15.3 Morozova et al. (2014)
PDYN Prodynorphin 20p13 Williams et al. (2007)
PEA15 Phosphoprotein enriched in astrocytes, 15-kDa 1q23.2 Liu et al. (2007)
PEBP1 Phosphatidylethanolamine-binding protein 1 12q24.23 Manzardo et al. (2014)
PGM2L1 Phosphoglucomutase 2-like 1 11q13.4 Flatscher-Bader et al. (2005)
PHF3 PHD (plant homeodomain) finger protein 3 6q12 Zuo et al. (2011)
PIBF1 Progesterone-induced blocking factor 1 13q22.1 Flatscher-Bader et al. (2005)
PIEZO2 Piezo-type mechanosensitive ion channel component 2 18p11.22 Manzardo et al. (2014)
PIPOX Pipecolic acid oxidase 17q11.2 Flatscher-Bader et al. (2005)
PKN1 Protein kinase N1 19p13.12 Guo et al. (2009)
PKNOX2 PBX(pre-B-cell leukemia homeobox)/knotted 1 homeobox 2 11q24.2 Bierut et al. (2010)
PLA2G1B Phospholipase A2, group IB (pancreas) 12q24.31 Mayfield et al. (2002)
PLCL1 Phospholipase C-like 1 2q33.1 Kapoor et al. (2013)
PLP1 Proteolipid protein 1 Xq22.2 Mayfield et al. (2002)
PML Promyelocytic leukemia 15q24.1 Flatscher-Bader et al. (2005)
PMP22 Peripheral myelin protein 22 17p12 Liu et al. (2004); Manzardo et al. (2014)
POLD2 Polymerase (DNA-directed), delta 2, regulatory subunit 7p13 Flatscher-Bader et al. (2005)
POMC Proopiomelanocortin 2p23.3 Zuo et al. (2011)
PPAN Peter pan, Drosophila, homolog of 19p13.2 Flatscher-Bader et al. (2005)
PRDX6 Peroxiredoxin 6 1q25.1 Guo et al. (2009)
PRKCA Protein kinase C, alpha 17q24.2 Morozova et al. (2014)
PSMB2 Proteasome subunit, beta type, 2 1p34.3 Liu et al. (2006)
PTP4A1 Protein-tyrosine phosphatase, type 4A, 1 6q12 Zuo et al. (2009)
PTPRD Protein-tyrosine phosphatase, receptor-type, delta 9p23 Morozova et al. (2012)
PURA Purine-rich element-binding protein A 5q31.2 Liu et al. (2004)
QDPR Quinoid dihydropteridine reductase 4p15.32 Joslyn et al. (2010); Yu et al. (2008)
RAB1A RAS-associated protein RAB1 2p14 Guo et al. (2009)
RAB11B RAB11B, member RAS oncogene family 19p13.2 Mayfield et al. (2002)
RAB3A RAS-associated protein RAB3A 19p13.11 Guo et al. (2009)
RANBP3L RAN (Ras-related nuclear protein) Binding Protein 3-like 5p13.2 Manzardo et al. (2014)
RASGRP3 RAS guanyl nucleotide-releasing protein 3 2p22.3 Manzardo et al. (2014)
RGS8 Regulator of G protein signaling 8 1q25.3 Flatscher-Bader et al. (2005)
RHOA RAS homolog gene family, member A 3p21.31 Flatscher-Bader et al. (2010)
RHOB RAS homolog gene family, member B 2p24.1 Flatscher-Bader et al. (2010)
RPE Ribulose 5-phosphate 3-epimerase 2q34 Flatscher-Bader et al. (2005)
RPL22 Ribosomal protein L22 1p36.31 Flatscher-Bader et al. (2005)
RPS29 Ribosomal protein S29 14q21.3 Flatscher-Bader et al. (2005)
RPS6KA5 Ribosomal protein S6 kinase, 90 kDa, polypeptide 5 14q32.11 Flatscher-Bader et al. (2005)
RTN1 Reticulon 1 14q23.1 Mayfield et al. (2002)
RTN4 Reticulon 4 2p16.1 Liu et al. (2007)
SAMHD1 SAM (sterile alpha-motif) domain and HD (Huntington disease) domain 1 20q11.23 Flatscher-Bader et al. (2005)
SCD Stearoyl-CoA desaturase 10q24.31 Liu et al. (2006)
SDC2 Syndecan 2 8q22.1 Mayfield et al. (2002)
SEMA3E Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3E 7q21.11 Kerner et al. (2011)
SEMA5A Semaphorin 5A 5p15.31 Wang et al. (2011b)
SERINC2 Serine incorporator 2 1p35.2 Zuo et al. (2013a)
SERTAD3 SERTA (SEI-1, RBT1, TARA) domain containing 3 19q13.2 Flatscher-Bader et al. (2005)
SESN2 Sestrin 2 1p35.3 Flatscher-Bader et al. (2005)
SGOL1 Shugoshin-like 1 3p24.3 Pan et al. (2013)
SHC3 SHC (Src homology 2 domain containing) transforming protein 3 9q22.1 Morozova et al. (2014)
SI Sucrase-isomaltase (alpha-glucosidase) 3q26.1 Guo et al. (2009)
SLC1A3 Solute carrier family 1 (glial high affinity glutamate transporter), member 3 5p13.2 Flatscher-Bader et al. (2005)
SLC12A2 Solute carrier family 12 (sodium/potassium/chloride transporter), member 2 5q23.3 Liu et al. (2006)
SLC30A5 Solute carrier family 30 (zinc transporter), member 5 5q13.1-q13.2 Hill et al. (2004); Flatscher-Bader et al. (2005)
SLC5A11 Solute carrier family 5 (sodium/glucose cotransporter), member 11 16p12.1 Manzardo et al. (2014)
SLC6A4 Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 17q11.2 Feinn et al. (2005)
SMARCA5 SWI/SNF (switch/sucrose nonfermentable) related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 5 4q31.21 Liu et al. (2006)
SMPD2 Sphingomyelin phosphodiesterase 2, neutral membrane 6q21 Liu et al. (2004)
SMPDL3A Sphingomyelin phosphodiesterase, acid-like, 3A 6q22.31 Liu et al. (2004)
SMPDL3B Sphingomyelin phosphodiesterase, acid-like, 3B 1p35.3 Liu et al. (2004)
SNCA Synuclein, alpha 4q22.1 Bönsch et al. (2005)
SOCS1 Suppressor of cytokine signaling 1 16p13.13 Guo et al. (2009)
SOX9 SRY (sex determining region Y)-box 9 17q24.3 Mayfield et al. (2002)
SPARC Secreted protein, acidic, cysteine-rich 5q33.1 Flatscher-Bader et al. (2010)
SPOCK1 Sparc/osteonectin, CWCV (cys–trp–cys–val) and kazal-like domains proteoglycan (testican) 1 5q31.2 Liu et al. (2006)
SPP1 Secreted phosphoprotein 1 4q22.1 Manzardo et al. (2014)
SRSF10 Splicing factor, serine/arginine-rich, 10 1p36.11 Flatscher-Bader et al. (2005)
ST18 Suppression of tumorigenicity 18, zinc finger 8q11.23 Manzardo et al. (2014)
STXBP2 Syntaxin binding protein 2 19p13.2 Mayfield et al. (2002)
SYN2 Synapsin II 3p25.2 Mayfield et al. (2002)
SYT1 Synaptotagmin 1 12q21.2 Flatscher-Bader et al. (2005)
TACR3 Tachykinin receptor 3 4q24 Foroud et al. (2008)
TAS2R16 Taste receptor, type 2, Member 16 7q31.32 Hinrichs et al. (2006)
TAS2R38 Taste receptor, type 2, Member 38 7q34 Wang et al. (2007)
TF Transferrin 3q22.1 Liu et al. (2004)
TGFB1 Transforming growth factor, beta-1 19q13.2 Mayfield et al. (2002)
THRB Thyroid hormone receptor, beta 3p24.2 Mayfield et al. (2002)
THSD7B Thrombospondin, type I, domain containing 7B 2q22.1 Wang et al. (2011b)
TIMM10B Translocase of inner mitochondrial membrane 10 homolog B (yeast) 11p15.4 Flatscher-Bader et al. (2005)
TIMP1 TIMP (human tissue inhibitor of metalloproteinase) Metallopeptidase Inhibitor 1 Xp11.23 Mayfield et al. (2002)
TIMP2 Tissue inhibitor of metallopeptidase 2 17q25.3 Liu et al. (2006)
TIMP3 Tissue inhibitor of metallopeptidase 3 22q12.3 Flatscher-Bader et al. (2005)
TIPARP TCDD (tetrachlorodibenzo-p-dioxin)-inducible poly(ADP-ribose) polymerase 3q25.31 Wang et al. (2011a)
TKT Transketolase 3p21.1 Liu et al. (2006)
TMED10 Transmembrane emp24-like trafficking protein 10 (yeast) 14q24.3 Mayfield et al. (2002)
TMEM63A Transmembrane protein 63A 1q42.12 Manzardo et al. (2014)
TMEM108 Transmembrane protein 108 3q22.1 Heath et al. (2011)
TMX1 Thioredoxin-related transmembrane protein 1 14q22.1 Flatscher-Bader et al. (2005)
TPI1 Triosephosphate isomerase 1 12p13.31 Liu et al. (2006)
TSPAN7 Tetraspanin 7 Xp11.4 Liu et al. (2007)
TTC12 Tetratricopeptide repeat domain-containing protein 12 11q23.2 Yang et al. (2008)
TXN Thioredoxin 9q31.3 Flatscher-Bader et al. (2005)
TUBGCP2 Tubulin, gamma complex associated protein 2 10q26.3 Mayfield et al. (2002)
TULP1 Tubby like protein 1 6p21.31 Mayfield et al. (2002)
UBP1 Upstream binding protein 1 3p22.3 Flatscher-Bader et al. (2005)
UGT8 Uridine diphosphate glycosyltransferase 8 4q26 Manzardo et al. (2014)
ULK2 Unc51-like kinase 2 17p11.2 Liu et al. (2006)
UPP1 Uridine phosphorylase 1 7p12.3 Flatscher-Bader et al. (2005)
UQCRC2 Ubiquinol-cytochrome c reductase core protein II 16p12.2 Liu et al. (2006)
UQCRFS1 Ubiquinol-cytochrome C reductase, Rieske iron–sulfur polypeptide 1 19q12 Liu et al. (2006)
UROD Uroporphyrinogen decarboxylase 1p34.1 Flatscher-Bader et al. (2005)
USH2A Usher syndrome, type IIA 1q41 Morozova et al. (2012)
UTP20 Small subunit (SSU) processome component, homolog (yeast) 12q23.2 Kapoor et al. (2014)
VAMP3 Vesicle-associated membrane protein 3 1p36.23 Mayfield et al. (2002)
VCP Valosin-containing protein 9p13.3 Guo et al. (2009)
WASF1 Wiskott–Aldrich syndrome protein family, member 1 6q21 Flatscher-Bader et al. (2005)
WIF1 WNT (wingless-type MMTV integration site family) inhibitory factor 1 12q14.3 Manzardo et al. (2014)
XRCC5 X-ray repair, complementing defective, in Chinese hamster cells 5 (double-strand-break rejoining) 2q35 Joslyn et al. (2010); Yu et al. (2008)
ZBTB11 Zinc finger and BTB domain containing 11 3q12.3 Flatscher-Bader et al. (2005)
ZBTB49 Zinc finger and BTB domain containing 49 4p16.3 Flatscher-Bader et al. (2005)
ZNF24 Zinc finger protein 24 18q12.2 Flatscher-Bader et al. (2005)
ZSCAN32 Zinc finger and SCAN domain containing 32 16p13.3 Flatscher-Bader et al. (2005)
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Fig. 1.

Fig. 1.

Fig. 1.

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High resolution human chromosome ideograms (850 band level) with alcoholism gene symbols positioned at the chromosome band location. The upper ‘p’ and lower ‘q’ arms for each chromosome are separated by the centromere area highlighted in black. The gene symbol in alphabetical order, expanded name of the gene and precise chromosome band position are found in Table 1.

3. Discussions and conclusion

Decades of intensive research involving international collaborative networks utilizing large databases and tissue banks and advanced genetic technology and bioinformatics have led to significant discoveries in recognition of genetic variants and biomarkers implicated in the causation and course of alcoholism. Improved commercial platforms available for alcoholism research with potential application in the clinical setting have permitted the identification and characterization of the molecular signatures for novel or disturbed gene or exon expression and disease-specific profiles and patterns of interconnected disturbed gene pathways for alcoholism and other psychiatric or aberrant behavioral disorders in a growing body of genetic data and evidence. Significant discoveries have been made using microarray technology and now next generation sequencing with readily available tissue such as peripheral blood, autopsy specimens, established lymphoblastoid cell lines and/or saliva hold promise for more advances in alcoholism biomarker research by enabling the identification of new, clinically relevant genes impacting causation and disease mechanisms stimulating discovery of treatment modalities.

We identified 337 clinically relevant or known gene biomarkers for alcoholism based on computer searches of key words from peer reviewed medical literature reports or nationally sponsored web sites. These genetic biomarkers may be causative in nature or transient reflecting physiological responses to alcohol use or environmental influences such as poor nutrition, sanitation, and exposure to other drugs, illnesses, and viruses, common in chronic alcoholism. Transient, potentially modifiable genomic imbalances are important considerations in discovery, treatment and assessment of phenotypic outcomes in alcoholism. Future studies should also consider the impact of copy number variation, segmental deletions and duplications and regions of homozygosity in the genome for determination of identical by descent for calculation of inbreeding coefficients or consanguinity status along with uniparental disomy of individual chromosomes and areas of genomic imprinting on alcoholism risk and course of illness.

Our summary of the current status and number of clinically relevant human genetic biomarkers associated with alcoholism — targeting disturbed brain networks along with their position on high resolution chromosome ideograms will enhance the development of genetic testing options including DNA or gene testing panels for alcoholism and encourage genetic counseling of family members with a high density of alcoholism in biological relatives. The number of genes identified may vary in future studies based upon size and selected subject characteristics, tissue type and genetic technique used. The authors encourage the use of this current collection of genetic biomarkers from brain in alcoholism in their evaluation of patients and families to improve diagnosis and genetic counseling of selected patients, at-risk individuals and their families.

Acknowledgments

We thank Lorie Gavulic for excellent artistic design and preparation of chromosome ideograms. Support for this study was made available by grants from the Hanlon Charitable Trust, NICHD 02528 and the Headley Family Scholarship.

Abbreviations:

COGA

collaborativestudyonthegeneticsofalcoholism

DNA

deoxyribonucleic acid

FDA

Food and Drug Administration

GWAS

genome-wide association studies

mRNA

messenger ribonucleic acid

SAGE

study of addiction: genetics and environment

SNPs

single nucleotide polymorphisms

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