Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.

paper Primary Public

Authors: Adkins, Amy E; Hack, Laura M; Bigdeli, Tim B; Williamson, Vernell S; McMichael, G Omari; Mamdani, Mohammed; Edwards, Alexis C; Aliev, Fazil; Chan, Robin F; Bhandari, Poonam; Raabe, Richard C; Alaimo, Joseph T; Blackwell, GinaMari G; Moscati, Arden; Poland, Ryan S; Rood, Benjamin; Patterson, Diana G; Walsh, Dermot; Collaborative Study of the Genetics of Alcoholism Consortium; Whitfield, John B; Zhu, Gu; Montgomery, Grant W; Henders, Anjali K; Martin, Nicholas G; Heath, Andrew C; Madden, Pamela A F; Frank, Josef; Ridinger, Monika; Wodarz, Norbert; Soyka, Michael; Zill, Peter; Ising, Marcus; Nöthen, Markus M; Kiefer, Falk; Rietschel, Marcella; German Study of the Genetics of Addiction Consortium; Gelernter, Joel; Sherva, Richard; Koesterer, Ryan; Almasy, Laura; Zhao, Hongyu; Kranzler, Henry R; Farrer, Lindsay A; Maher, Brion S; Prescott, Carol A; Dick, Danielle M; Bacanu, Silviu A; Mathies, Laura D; Davies, Andrew G; Vladimirov, Vladimir I; Grotewiel, Mike; Bowers, M Scott; Bettinger, Jill C; Webb, Bradley T; Miles, Michael F; Kendler, Kenneth S; Riley, Brien P
Year: 2017
Journal: Alcoholism, clinical and experimental research
PMID: 28226201
DOI: 10.1111/acer.13362
PMCID: PMC5404949

BACKGROUND: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. METHODS: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. RESULTS: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). CONCLUSIONS: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

Figure 1

Manhattan plot for case/control analysis of Alcohol Dependence (AD)Horizontal red line indicates genome-wide significance (5 × 10−8).

LLM interpretation

This is a Manhattan plot showing the results of a case/control analysis for Alcohol Dependence (AD). The x-axis represents chromosomes (1–21) and the y-axis represents the negative logarithm of the p-value ($-\log_{10}(p)$). A horizontal red line marks the genome-wide significance threshold at $5 \times 10^{-8}$, with a small cluster of data points on chromosome 2 exceeding this threshold.

Figure 2

Q-Q plot for final post-imputation dataset after all quality control (QC) and exclusionsGray shading indicates 95% confidence interval for expected values. The post-imputation lambda (1.046) and sample size-standardized lambda1000 (1.045) indicate there is little inflation of test statistics.

LLM interpretation

This is a Q-Q plot comparing observed $-\log_{10}(p)$ values against expected $-\log_{10}(p)$ values for a post-imputation dataset. The observed data points closely follow the red diagonal identity line for most of the distribution, with a slight upward deviation at higher values that remains largely within or near the gray 95% confidence interval. The plot includes annotations for genomic inflation factors, $\lambda = 1.046$ and $\lambda_{1000} = 1.045$.

Figure 3

LocusZoom plots of COL6A3, RYR3, KLF12 and LOC339975Genomewide significant results in COL6A3 (A) and three other regions of suggestive association supported by additional data, RYR3 (B), KLF12 (C) and LOC339975 (D).

LLM interpretation

This figure consists of four LocusZoom plots (A-D) showing genetic associations for the genes *COL6A3*, *RYR3*, *KLF12*, and *LOC339975*. Each plot displays $-\log_{10}(p\text{-values})$ on the y-axis against genomic position on the x-axis, with blue lines indicating recombination rates and colored dots representing linkage disequilibrium ($r^2$) relative to a lead SNP. Plot A shows a genome-wide significant peak for *COL6A3*, while plots B, C, and D show suggestive association peaks for their respective loci.

Figure 4

Mutations in C. elegans orthologs of human candidate genes cause ethanol response phenotypesSpeed of locomotion was measured at 10 and 30 minutes, and expressed as a percent of the untreated control speed. Control worms were tested simultaneously on the same plates. Worms were treated with 400 mM exogenous ethanol. The waxy cuticle of worms excludes most of the exogenous ethanol, tissue concentrations are approximately 12% of the exogenous dose (~48 mM). A, B, C: RNAi-induced gene knockdown reduced sensitivity to ethanol for C16E9.1 (a COL6A3 ortholog) but not for two other orthologous genes relative to untreated worms. D: Loss-of-function of the KLF12 ortholog, klf-3, prevented the development of acute functional tolerance between the 10- and 30-minute time points relative to wild-type N2. E, F: unc-68 mutant animals demonstrate reduced sensitivity to ethanol relative to wild-type N2. Statistical significance is shown for 2-way ANOVA followed by post-hoc comparisons across genotypes (*, p<0.05, **, p<0.01, ***, p<0.001).

LLM interpretation

This figure consists of six line graphs (A-F) plotting the speed of *C. elegans* (as a percentage of untreated controls) over time (10 and 30 minutes) following ethanol treatment. Panels A, B, and C compare RNAi-induced gene knockdowns to L4440 controls, with only *C16E9.1* showing a significant increase in speed at 10 minutes (*p<0.05). Panels D, E, and F compare mutant strains to wild-type (WT), showing that *klf-3* prevents the increase in speed between 10 and 30 minutes, while *unc-68* mutants exhibit significantly higher speeds at 30 minutes (E, **p<0.01) or at both time points (F, **p<0.01).

Figure 5

Bioinformatic analysis of correlation of Col6a3, Klf12 or Ryr3 expression with ethanol behaviors in C57BL/6J × DBA/2J recombinant inbred (BXD) mouse linesThe GeneNetwork (GN) web-based analysis platform was used to identify correlations between between basal expression levels of Col6a3, Klf12 or Ryr3 and ethanol behaviors. Panels A-D display Spearman ranked order correlations between microarray gene expression (x-axis) and behavioral phenotypes (y-axis). Col6a3 (probeset 1424131_at) in GN113 whole brain expression dataset showed significant positive correlation with total handling induced convulsion (HIC) score (sum of baseline subtracted HIC at 4, 6 and 7 hrs) after 4 g/kg intraperitoneal (IP) ethanol in males (GN record 11382; Panel A) and negative correlation with ethanol 2-bottle choice voluntary consumption (GN record 10479; Panel B). Klf12 basal expression in prefrontal cortex (GN135, probeset 1455521_at) was significantly positively correlated with locomotor activity 0–5 minutes after 2.25 g/kg IP ethanol (GN record 11708; Panel C) and in nucleus accumbens (GN156, probeset 1439827_s_at) was positively correlated with ethanol acute functional tolerance (GN record 10348; Panel D).

LLM interpretation

This figure consists of four scatter plots (A-D) showing Spearman ranked order correlations between gene expression (x-axis) and ethanol-related behavioral phenotypes (y-axis) in BXD mouse lines. Panels A and B show that *Col6a3* whole brain expression is significantly positively correlated with total HIC score ($\rho = 0.959, p = 1.08\text{E-}09$) and negatively correlated with ethanol 2-bottle choice preference ($\rho = -0.569, p = 1.24\text{E-}02$). Panels C and D show that *Klf12* expression is significantly positively correlated with locomotor activity in the prefrontal cortex ($\rho = 0.756, p = 1.69\text{E-}05$) and acute functional tolerance in the nucleus accumbens ($\rho = 0.560, p = 3.01\text{E-}03$).

Figure 6

Expression of long noncoding RNA LOC339975 in human post-mortem nucleus accumbens (NAc) and dorsolateral pre-frontal cortex (PFC) stratified by diagnostic status and by genotypeControl mean RIN was 5.6 (SD=1.8), case mean RIN was 5.8 (SD=1.5), and did not differ between cases and controls (Mann-Whitney p=0.78). Samples that did not amplify (NAc, N=13; PFC, N=24) and 4 samples missing rs11726136 genotypes were excluded. Case:control comparisons of LOC339975 expression in A. 34 case and 35 control NAc samples, and B. 28 case and 30 control PFC samples. There were no significant differences in expression between diagnostic groups. Genotypic comparisons of LOC339975 expression in C. 58 reference (T/T) homozygote and 7 T/G heterozygote NAc samples, and D. 50 T/T homozygote and 5 T/G heterozygote PFC samples. While no significant differences in expression by genotype were observed in the PFC, NAc expression was significantly reduced in carriers of the associated non-reference G allele compared to reference allele homozygotes (F=9.72, p=0.003).

LLM interpretation

This figure consists of four box plots showing the expression of long noncoding RNA LOC339975 in the nucleus accumbens (NAc; A, C) and dorsolateral pre-frontal cortex (PFC; B, D). Panels A and B compare expression between "Controls" and "Cases," showing no significant differences (p=0.75 and p=0.23, respectively). Panels C and D compare expression by genotype (AA vs. Het/-B) for rs11726136, revealing a significant reduction in expression in the NAc for the Het/-B group (p=0.003), while no significant difference is seen in the PFC (p=0.54).

#	Section	Preview
0	Introduction	Alcohol dependence (AD) is a major public health burden with substantial costs for individuals and…
1	Introduction	Prior genome-wide association studies (GWAS) of AD and alcohol-related phenotypes in European…
2	Introduction	To identify genes influencing alcohol-related phenotypes, we conducted a GWAS of AD. To maximize…
3	Introduction	Well-developed experimental approaches can test directly whether changes in candidate genes impact…
4	Introduction	To provide functional support for GWAS candidates, we tested whether perturbation of orthologous…
5	Materials and Methods — GWAS Discovery Sample	Participants in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) were recruited in…
6	Materials and Methods — GWAS Discovery Sample	2048 DNA samples from healthy, unpaid volunteers donating blood at the Irish Blood Transfusion…
7	Materials and Methods — GWAS Genotyping, Quality Control and Imputation	Genomic DNAs passing quality control (QC) standards were genotyped on Affymetrix v6.0 SNP arrays.…
8	Materials and Methods — GWAS Statistical Analyses	We tested individual SNPs for association by Modified Quasi-Likelihood Score (MQLS) (Thornton and…
9	Materials and Methods — Selection for Further Study	We calculated false discovery rate (FDR) q-values (Storey and Tibshirani, 2003) for all SNPs to…
10	Materials and Methods — Assessment of Variants for Potential Functional Impact	For variants with q<0.1, we assessed variant potential to impact function either directly or via LD…
11	Materials and Methods — GWAS Replication	We conducted replication analyses in N=15,496 European subjects from three AD case-control samples…
12	Materials and Methods — Invertebrate model organism studies — C. elegans studies	A single, continuous acute exposure of C. elegans to 400 mM exogenous ethanol yields an internal…
13	Materials and Methods — Invertebrate model organism studies — C. elegans studies — C. elegans strains	C. elegans strains were maintained as previously described (Brenner, 1974). Strains used in these…
14	Materials and Methods — Invertebrate model organism studies — C. elegans studies — RNAi treatment	RNA interference (RNAi) induction and locomotion assays were performed as previously described…
15	Materials and Methods — Invertebrate model organism studies — C. elegans studies — Locomotion tracking	Locomotion was assayed as previously described (Bettinger et al., 2012). Ten worms for each strain…
16	Materials and Methods — Invertebrate model organism studies — C. elegans studies — Locomotion tracking	Columbia) on an Olympus SZX-7 microscope. Movies were analyzed using ImagePro Plus (6.2)…
17	Materials and Methods — Invertebrate model organism studies — C. elegans studies — Statistical analysis	Comparisons were made of animals tested in identical conditions. Relative speeds (treated/untreated…
18	Materials and Methods — Invertebrate model organism studies — Drosophila studies	Only one candidate locus (RYR3) had both a Drosophila ortholog and genetic reagents available.…
19	Materials and Methods — Mammalian model organism studies — Mouse studies	We queried selected candidate genes for localization to ethanol behavioral QTL intervals using the…

Citation	PMID	DOI	Status
Alaimo, JT et al., Alcohol Clin Exp Res, 2012, Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans	22486589	10.1111/j.1530-0277.2012.01799.x	Cited
Alam, T et al., PLoS One, 2014, Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes	25275320	10.1371/journal.pone.0109443	Cited
Atsma, F et al., Transfusion, 2011, Cardiovascular and demographic characteristics in whole blood and plasma donors: results from the Donor InSight study	20804526	10.1111/j.1537-2995.2010.02867.x	Cited
Aulchenko, YS et al., Bioinformatics, 2007, GenABEL: an R library for genome-wide association analysis	17384015	10.1093/bioinformatics/btm108	Cited
Bahi, A et al., Behav Brain Res, 2012, Involvement of tissue plasminogen activator “tPA” in ethanol-induced locomotor sensitization and conditioned-place preference	21945298	10.1016/j.bbr.2011.09.024	Cited
Baik, I et al., Am J Clin Nutr, 2011, Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men	21270382	10.3945/ajcn.110.001776	Cited
Bargmann, CI, Science, 1998, Neurobiology of the Caenorhabditis elegans genome	9851919	10.1126/science.282.5396.2028	Cited
Barry, G et al., Mol Psychiatry, 2014, The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing	23628989	10.1038/mp.2013.45	Cited
Barry, G et al., Sci Rep, 2017, The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states	28054653	10.1038/srep40127	Cited
Bergeson, SE et al., Mamm Genome, 2003, Chromosomal loci influencing chronic alcohol withdrawal severity	12925894	10.1007/s00335-002-2254-4	Cited
Bettinger, JC et al., PLoS One, 2012, Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans	22574115	10.1371/journal.pone.0035192	Cited
Bhandari, P et al., Genes Brain Behav, 2012, Chloride intracellular channels modulate acute ethanol behaviors in Drosophila, Caenorhabditis elegans and mice	22239914	10.1111/j.1601-183X.2012.00765.x	Cited
Bond, J et al., Alcohol Clin Exp Res, 2010, The relationship between self-reported drinking and BAC level in emergency room injury cases: is it a straight line?	20374201	10.1111/j.1530-0277.2010.01188.x	Cited
Brenner, S, Genetics, 1974, The genetics of Caenorhabditis elegans	4366476	10.1093/genetics/77.1.71	Cited
Browning, BL et al., Am J Hum Genet, 2009, Simultaneous genotype calling and haplotype phasing improves genotype accuracy and reduces false-positive associations for genome-wide association studies	19931040	10.1016/j.ajhg.2009.11.004	Cited
Brownlee, DJ et al., Trends Neurosci, 1999, Exploring the neurotransmitter labyrinth in nematodes	10088995	10.1016/s0166-2236(98)01281-8	Cited
Bucholz, KK et al., J Stud Alcohol, 1994, A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA	8189735	10.15288/jsa.1994.55.149	Primary
Chan, RF et al., Alcohol Clin Exp Res, 2014, Contrasting Influences of Drosophila white/mini-white on Ethanol Sensitivity in Two Different Behavioral Assays	24890118	10.1111/acer.12421	Cited
Cotton, NS, J Stud Alcohol, 1979, The familial incidence of alcoholism: a review	376949	10.15288/jsa.1979.40.89	Cited
Crabbe, JC, Am J Med Genet, 2002, Alcohol and genetics: new models	12457395	10.1002/ajmg.b.10984	Cited
Davies, AG et al., Cell, 2003, A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans	14675531	10.1016/s0092-8674(03)00979-6	Cited
Davies, AG et al., Neuron, 2004, Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. elegans	15182714	10.1016/j.neuron.2004.05.004	Cited
Edenberg, HJ et al., Alcohol Clin Exp Res, 2010, Genome-wide association study of alcohol dependence implicates a region on chromosome 11	20201924	10.1111/j.1530-0277.2010.01156.x	Primary
Faghihi, MA et al., Nat Med, 2008, Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase	18587408	10.1038/nm1784	Cited
Frank, J et al., Addict Biol, 2012, Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster	22004471	10.1111/j.1369-1600.2011.00395.x	Cited
French, RL et al., Proc Natl Acad Sci U S A, 2009, Glycogen synthase kinase-3/Shaggy mediates ethanol-induced excitotoxic cell death of Drosophila olfactory neurons	19923438	10.1073/pnas.0910813106	Cited
Gass, JT et al., Biochem Pharmacol, 2008, Glutamatergic substrates of drug addiction and alcoholism	17706608	10.1016/j.bcp.2007.06.039	Cited
Gelernter, J et al., Mol Psychiatry, 2014, Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci	24166409	10.1038/mp.2013.145	Primary
Grotewiel, M et al., Alcohol Clin Exp Res, 2015, Drosophila and Caenorhabditis elegans as Discovery Platforms for Genes Involved in Human Alcohol Use Disorder	26173477	10.1111/acer.12785	Cited
Guttman, M et al., Nature, 2011, lincRNAs act in the circuitry controlling pluripotency and differentiation	21874018	10.1038/nature10398	Cited
Hangauer, MJ et al., PLoS Genet, 2013, Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs	23818866	10.1371/journal.pgen.1003569	Cited
Harford, TC et al., J Psychiatr Res, 2013, DSM-IV personality disorders and associations with externalizing and internalizing disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions	23932575	10.1016/j.jpsychires.2013.07.016	Cited
Hasin, DS et al., Arch Gen Psychiatry, 2007, Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions	17606817	10.1001/archpsyc.64.7.830	Cited
Heath, AC et al., Biol Psychiatry, 2011, A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications	21529783	10.1016/j.biopsych.2011.02.028	Cited
Howie, BN et al., PLoS Genet, 2009, A flexible and accurate genotype imputation method for the next generation of genome-wide association studies	19543373	10.1371/journal.pgen.1000529	Cited
Johnson, AD et al., Bioinformatics, 2008, SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap	18974171	10.1093/bioinformatics/btn564	Cited
Joslyn, G et al., Alcohol Clin Exp Res, 2010, Human variation in alcohol response is influenced by variation in neuronal signaling genes	20201926	10.1111/j.1530-0277.2010.01152.x	Cited
Kaletta, T et al., Nat Rev Drug Discov, 2006, Finding function in novel targets: C. elegans as a model organism	16672925	10.1038/nrd2031	Cited
Kamath, RS et al., Genome Biol, 2001, Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans	11178279	10.1186/gb-2000-2-1-research0002	Cited
Kapfhamer, D et al., Genes Brain Behav, 2008, Loss of RAB-3/A in Caenorhabditis elegans and the mouse affects behavioral response to ethanol	18397381	10.1111/j.1601-183X.2008.00404.x	Cited
Kendler, KS et al., Nat Neurosci, 2012, Recent advances in the genetic epidemiology and molecular genetics of substance use disorders	22281715	10.1038/nn.3018	Cited
Kerin, T et al., Sci Transl Med, 2012, A noncoding RNA antisense to moesin at 5p14.1 in autism	22491950	10.1126/scitranslmed.3003479	Cited
Kirstein, SL et al., J Pharmacol Exp Ther, 2002, Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice	12183685	10.1124/jpet.302.3.1238	Cited
Kuo, PH et al., Alcoholism-Clinical and Experimental Research, 2006, Identification of Susceptibility Loci for Alcohol-related Traits in the Irish-Affected Sib Pair Study of Alcohol Dependence	17067344	10.1111/j.1530-0277.2006.00217.x	Cited
Kurokawa, K et al., Alcohol Clin Exp Res, 2013, Dopamine D1 receptor signaling system regulates ryanodine receptor expression in ethanol physical dependence	23278119	10.1111/acer.12036	Cited
Kurokawa, K et al., J Neurochem, 2010, Regulation of ryanodine receptors by dopamine D1 receptors during methamphetamine-induced place conditioning	20854431	10.1111/j.1471-4159.2010.07010.x	Cited
Kurokawa, K et al., J Pharmacol Sci, 2011, Dopamine D(1) receptors participate in cocaine-induced place preference via regulation of ryanodine receptor expression	21897053	10.1254/jphs.11106fp	Cited
Li, MJ et al., Nucleic Acids Res, 2013, GWAS3D: Detecting human regulatory variants by integrative analysis of genome-wide associations, chromosome interactions and histone modifications	23723249	10.1093/nar/gkt456	Cited
Lifshitz, LM et al., J Gen Physiol, 2011, Spatial organization of RYRs and BK channels underlying the activation of STOCs by Ca(2+) sparks in airway myocytes	21746845	10.1085/jgp.201110626	Cited
Liu, J et al., Mol Pharmacol, 2008, Ethanol modulates BKCa channels by acting as an adjuvant of calcium	18552122	10.1124/mol.108.048694	Cited
Lubbers, BR et al., Prog Brain Res, 2014, Neural ECM in addiction, schizophrenia, and mood disorder	25410362	10.1016/B978-0-444-63486-3.00012-8	Cited
Martin, GE et al., Proc Natl Acad Sci U S A, 2008, Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol	18981408	10.1073/pnas.0801068105	Cited
Mathies, LD et al., Proc Natl Acad Sci U S A, 2015, SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans	25713357	10.1073/pnas.1413451112	Cited
Matthews, DJ et al., Drug Discov Today, 2001, Using model-system genetics for drug-based target discovery	11165187	10.1016/s1359-6446(00)01612-3	Cited
Mercer, TR et al., Proc Natl Acad Sci U S A, 2008, Specific expression of long noncoding RNAs in the mouse brain	18184812	10.1073/pnas.0706729105	Cited
Metten, P et al., Mamm Genome, 1998, High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption	9880664	10.1007/s003359900911	Cited
Nature, 2007, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls	17554300	10.1038/nature05911	Cited
Nature, 2010, A map of human genome variation from population-scale sequencing	20981092	10.1038/nature09534	Cited
Park, BL et al., Hum Genet, 2013, Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication	23456092	10.1007/s00439-013-1281-8	Cited
Pawlak, R et al., Proc Natl Acad Sci U S A, 2005, Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors	15630096	10.1073/pnas.0406454102	Cited
Philip, VM et al., Genes Brain Behav, 2010, High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains	19958391	10.1111/j.1601-183X.2009.00540.x	Cited
Phillips, TJ et al., Alcohol Clin Exp Res, 1994, Localization of genes affecting alcohol drinking in mice	7978106	10.1111/j.1530-0277.1994.tb00062.x	Cited
Prescott, CA et al., Alcohol Clin Exp Res, The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history	15770118	10.1097/01.alc.0000156085.50418.07	Cited
Prescott, CA et al., Am J Med Genet B Neuropsychiatr Genet, The Washington University Twin Study of alcoholism	15704214	10.1002/ajmg.b.30124	Cited
Quillen, EE et al., Am J Med Genet B Neuropsychiatr Genet, 2014, ALDH2 is associated to alcohol dependence and is the major genetic determinant of “daily maximum drinks” in a GWAS study of an isolated rural Chinese sample	24277619	10.1002/ajmg.b.32213	Cited
Rice, DP, Proc Assoc Am Physicians, 1999, Economic costs of substance abuse, 1995	10220806	10.1046/j.1525-1381.1999.09254.x	Cited
Riley, B et al., Mol Psychiatry, 2010, Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample	19844207	10.1038/mp.2009.109	Cited
Roberts, TC et al., Philos Trans R Soc Lond B Biol Sci, 2014, The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease	25135968	10.1098/rstb.2013.0507	Cited
Schuckit, MA et al., J Stud Alcohol, 1997, The relationship between Self-Rating of the Effects of alcohol and alcohol challenge results in ninety-eight young men	9203121	10.15288/jsa.1997.58.397	Primary
Schuierer, M et al., J Biol Chem, 2001, Induction of AP-2alpha expression by adenoviral infection involves inactivation of the AP-2rep transcriptional corepressor CtBP1	11373277	10.1074/jbc.M100070200	Cited
Schumann, G et al., Proc Natl Acad Sci U S A, 2011, Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption	21471458	10.1073/pnas.1017288108	Primary
Sigvardsson, S et al., Arch Gen Psychiatry, 1996, Replication of the Stockholm Adoption Study of alcoholism. Confirmatory cross-fostering analysis	8694681	10.1001/archpsyc.1996.01830080033007	Cited
Smith, AW et al., Neurobiol Learn Mem, 2011, Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems	21530666	10.1016/j.nlm.2011.04.011	Cited
Storey, JD et al., Proc Natl Acad Sci U S A, 2003, Statistical significance for genomewide studies	12883005	10.1073/pnas.1530509100	Cited
Thornton, T et al., Am J Hum Genet, 2007, Case-control association testing with related individuals: a more powerful quasi-likelihood score test	17668381	10.1086/519497	Cited
Treutlein, J et al., Arch Gen Psychiatry, 2009, Genome-wide association study of alcohol dependence	19581569	10.1001/archgenpsychiatry.2009.83	Cited
Volkow, ND et al., Annu Rev Pharmacol Toxicol, 2012, Addiction circuitry in the human brain	21961707	10.1146/annurev-pharmtox-010611-134625	Cited
Wang, JC et al., Mol Psychiatry, 2013, A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53	23089632	10.1038/mp.2012.143	Primary
Wang, X et al., Nat Commun, 2016, Joint mouse-human phenome-wide association to test gene function and disease risk	26833085	10.1038/ncomms10464	Cited
Willer, CJ et al., Bioinformatics, 2010, METAL: fast and efficient meta-analysis of genomewide association scans	20616382	10.1093/bioinformatics/btq340	Cited
Wolen, AR et al., PLoS One, 2012, Genetic dissection of acute ethanol responsive gene networks in prefrontal cortex: functional and mechanistic implications	22511924	10.1371/journal.pone.0033575	Cited
Ystrom, E et al., Alcohol Clin Exp Res, 2011, Alcohol dependence in men: reliability and heritability	21676009	10.1111/j.1530-0277.2011.01518.x	Cited

In this knowledge base

Title	Year	PMID
A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity.	2018	29623680
Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.	2018	29405378

External

Title	Authors	Journal	Year	Link
Identifying compounds to treat opiate use disorder by leveraging multi-omic data integration and multiple drug repurposing databases.	Stratford JK et al.	—	2025	→
Modeling Brain Gene Expression in Alcohol Use Disorder with Genetic Animal Models.	Hitzemann R et al.	—	2025	→
Nicotine Motivated Behavior in <i>C. elegans</i>.	Salim C et al.	—	2024	→
Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models.	Bhandari A et al.	—	2024	→
Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes.	Brocato ER et al.	—	2023	→
Contagious Transmission in a Swedish National Sample of Alcohol Use Disorders as a Function of Geographical Proximity Among Siblings and Propinquity-of-Rearing Defined Acquaintances.	Kendler KS et al.	—	2023	→
Functional roles, regulatory mechanisms and theranostics applications of ncRNAs in alcohol use disorder.	Wang JQ et al.	—	2023	→
GeneCup: mining PubMed and GWAS catalog for gene-keyword relationships.	Gunturkun MH et al.	—	2022	→
Long Non-Coding RNAs: The New Frontier into Understanding the Etiology of Alcohol Use Disorder.	Denham AN et al.	—	2022	→
mRNA and long non-coding RNA expression profiles of rotator cuff tear patients reveal inflammatory features in long head of biceps tendon.	Ren YM et al.	—	2022	→
Epigenetic and non-coding regulation of alcohol abuse and addiction.	Farris SP et al.	—	2021	→
ERR and dPECR Suggest a Link Between Neuroprotection and the Regulation of Ethanol Consumption Preference.	Velo Escarcena L et al.	—	2021	→
Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use.	Huggett SB et al.	—	2021	→
Interpretation of psychiatric genome-wide association studies with multispecies heterogeneous functional genomic data integration.	Reynolds T et al.	—	2021	→
Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons.	Podvin S et al.	—	2021	→
On the Use of Heterogeneous Stock Mice to Map Transcriptomes Associated With Excessive Ethanol Consumption.	Hitzemann R et al.	—	2021	→
Transcriptional analysis of the response of C. elegans to ethanol exposure.	Sterken MG et al.	—	2021	→
Alternative methanogenesis - Methanogenic potential of organosulfur administration.	Varga P et al.	—	2020	→
Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence.	Drake J et al.	—	2020	→
Dietary yeast influences ethanol sedation in Drosophila via serotonergic neuron function.	Schmitt RE et al.	—	2020	→
Flying Together: <i>Drosophila</i> as a Tool to Understand the Genetics of Human Alcoholism.	Lathen DR et al.	—	2020	→
Within-Family Transmission of Alcohol Use Disorder in Parent-Offspring, Sibling, and Cousin Pairs: A Contagion Model.	Kendler KS et al.	—	2020	→
A Pathway-Based Genomic Approach to Identify Medications: Application to Alcohol Use Disorder.	Ferguson LB et al.	—	2019	→
Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B/Mef2 in Alcohol Sensitivity.	Schmitt RE et al.	—	2019	→
Cross-species alcohol dependence-associated gene networks: Co-analysis of mouse brain gene expression and human genome-wide association data.	Mignogna KM et al.	—	2019	→
The expanded BXD family of mice: A cohort for experimental systems genetics and precision medicine	Ashbrook DG et al.	—	2019	—
The importance of long non-coding RNAs in neuropsychiatric disorders.	Hosseini E et al.	—	2019	→
Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms.	Scholz H	—	2019	→
A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity.	Schuckit MA	—	2018	→
A non-coding CRHR2 SNP rs255105, a cis-eQTL for a downstream lincRNA AC005154.6, is associated with heroin addiction.	Levran O et al.	—	2018	→
A Whole Methylome Study of Ethanol Exposure in Brain and Blood: An Exploration of the Utility of Peripheral Blood as Proxy Tissue for Brain in Alcohol Methylation Studies.	Clark SL et al.	—	2018	→
Cross-species molecular dissection across alcohol behavioral domains.	Farris SP et al.	—	2018	→
Gender-Specific Effects of Selection for Drinking in the Dark on the Network Roles of Coding and Noncoding RNAs.	Iancu OD et al.	—	2018	→
Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.	Savage JE et al.	—	2018	→
Xenopus embryos to study fetal alcohol syndrome, a model for environmental teratogenesis.	Fainsod A et al.	—	2018	→