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
20	Materials and Methods — Mammalian model organism studies — Mouse studies	We used the single Col6a3 probeset (1424131_at_A). We selected the most representative probeset…
21	Materials and Methods — Mammalian model organism studies — Mouse studies	A total of 5134 traits are present in GeneNetwork, but they are not all independent because of both…
22	Materials and Methods — Rat studies	We studied the effect of pharmacological antagonism of ryanodine receptors on ethanol…
23	Materials and Methods — Human post-mortem studies	PFC and NAc tissues from 41 AD cases and 41 controls were provided by the New South Wales Tissue…
24	Results — Irish case/control discovery dataset	After all QC, the dataset consisted of 706 probands and affected siblings, 464 (65.7%) male and 242…
25	Results — Variation in COL6A3 is associated with AD	In single marker analyses, 14 SNPs defining two independent genomic intervals achieve genome-wide…
26	Results — Additional loci are suggestively associated with AD	A total of 28 SNPs in 7 LD-independent loci had q<0.1 (Table 1). These include SNPs in two loci with…
27	Results — Additional loci are suggestively associated with AD	If the Fisher’s combined probability test from GWAS3D provided increased evidence based on…
28	Results — Additional loci are suggestively associated with AD	The signals at 3q26.31 (Supplementary Figure S5A) and KLF12 (Figure 3C) are with single imputed SNPs…
29	Results — Human replication	A total of 274 SNPs had discovery q<0.3, and were included in replication. SNAP analysis indicated…
30	Results — Human replication	We also assessed evidence in our discovery data for association with loci identified in prior AD…
31	Results — Secondary analyses	Results of secondary analyses of discovery GWAS data are shown in Supplementary Table S3 (gene-based…
32	Results — Selection for functional studies	We undertook functional studies of four candidate loci, COL6A3 and LOC339975 based on the GWS…
33	Results — COL6A3: Regulation of ethanol sensitivity in C. elegans and correlation with handling-induced convulsions in mice	We tested three C. elegans genes with equally high orthology to human COL6A3 for effects on initial…
34	Results — COL6A3: Regulation of ethanol sensitivity in C. elegans and correlation with handling-induced convulsions in mice	In mice, Col6a3 is located within the Alcw5 QTL interval (MGI:3037048) for handling-induced…
35	Results — COL6A3: Regulation of ethanol sensitivity in C. elegans and correlation with handling-induced convulsions in mice	In GeneNetwork, the strongest correlation observed for mouse Col6a3 basal whole brain expression…
36	Results — KLF12: Regulation of acute functional tolerance to ethanol in C. elegans and gene expression correlation with locomotor activity in mice	There is significant prior evidence for a role of KLF12 in ethanol response behaviors across…
37	Results — KLF12: Regulation of acute functional tolerance to ethanol in C. elegans and gene expression correlation with locomotor activity in mice	We tested a strong loss-of-function allele in klf-3. There was no difference in initial sensitivity…
38	Results — KLF12: Regulation of acute functional tolerance to ethanol in C. elegans and gene expression correlation with locomotor activity in mice	Based on patterns of regulation of mouse Klf12 by ethanol (Wolen et al., 2012), we analyzed…
39	Results — RYR3: Regulation of initial sensitivity to ethanol in C. elegans, rapid tolerance to ethanol in Drosophila, and motivation to self administer alcohol in rats	Previous studies have implicated ryanodine receptors (RyR) in ethanol phenotypes: in humans, RYR3…

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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	→