Genome-wide association discoveries of alcohol dependence.

paper Cited Public

Authors: Zuo, Lingjun; Lu, Lingeng; Tan, Yunlong; Pan, Xinghua; Cai, Yiqiang; Wang, Xiaoping; Hong, Jiang; Zhong, Chunlong; Wang, Fei; Zhang, Xiang-Yang; Vanderlinden, Lauren A; Tabakoff, Boris; Luo, Xingguang
Year: 2014
Journal: The American journal on addictions
PMID: 25278008
DOI: 10.1111/j.1521-0391.2014.12147.x
PMCID: PMC4187224

OBJECTIVE: To report the genome-wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions. METHODS: We searched in PubMed for all genome-wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: genome-wide significant associations in an individual sample, the combined samples, or the meta-analysis (p < 5 × 10(-8) ); top-ranked associations in an individual sample (p < 10(-5) ) that were nominally replicated in other samples (p < .05); and nominally replicable associations across at least three independent GWAS samples (p < .05). These results were meta-analyzed. cis-eQTLs in human, RNA expression in rat and mouse brains and bioinformatics properties of all of these risk variants were analyzed. RESULTS: The variants located within the alcohol dehydrogenase (ADH) cluster were significantly associated with alcohol dependence at the genome-wide level (p < 5 × 10(-8) ) in at least one sample. Some associations with the ADH cluster were replicable across six independent GWAS samples. The variants located within or near SERINC2, KIAA0040, MREG-PECR or PKNOX2 were significantly associated with alcohol dependence at the genome-wide level (p < 5 × 10(-8) ) in meta-analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within NRD1, GPD1L-CMTM8 or MAP3K9-PCNX were suggestive (5 × 10(-8) < p < 10(-5) ) in some samples, and nominally replicable in other samples. The associations with the variants at HTR7 and OPA3 were nominally replicable across at least three independent GWAS samples (10(-5) < p < .05). Some risk variants at the ADH cluster, SERINC2, KIAA0040, NRD1, and HTR7 had potential biological functions. CONCLUSION: The most robust risk locus was the ADH cluster. SERINC2, KIAA0040, NRD1, and HTR7 were also likely to play important roles in alcohol dependence. PKNOX2, MREG, PECR, GPD1L, CMTM8, MAP3K9, PCNX, and OPA3 might play less important roles in risk for alcohol dependence based on the function analysis. This conclusion will significantly contribute to the post-GWAS follow-up studies on alcohol dependence.

#	Section	Preview
0	Introduction	Alcohol dependence is a chronic but often progressive disease that includes problems in controlling…
1	Introduction	The development of alcohol dependence has been proposed to be related to the metabolism of alcohol,…
2	Introduction	GWASs reported numerous associations. Correction for multiple testing at genome-wide level…
3	Materials and Methods	We presented previous GWAS findings in Table 1. Some previous GWASs combined heterogeneous samples…
4	Materials and Methods — Selection of GWASs and presentation of findings	We searched in PubMed and reviewed 45 GWASs of alcohol dependence (i.e., “alcoholism”,…
5	Materials and Methods — Meta-analysis	To combine the effects of completely independent samples (underlined in Table 1), meta-analysis…
6	Materials and Methods — Meta-analysis	reference allele. Next, an overall z-statistic and combined p-value are then calculated from a…
7	Materials and Methods — Cis-eQTL analysis	There is a substantial gap between SNP-alcohol dependence associations and understanding how these…
8	Materials and Methods — Cis-eQTL analysis	80 peripheral blood mononuclear cell (PBMC) samples collected from living healthy donors (15). The…
9	Materials and Methods — Rat brain transcriptome analysis	We also assessed the mRNA expression of these risk genes in brains of two strains of rats (i.e.,…
10	Materials and Methods — Bioinformatics analysis	All of the risk SNPs listed in Table 1 were analyzed using UCSC Genome Browser data or other…
11	Materials and Methods — SNP-disease association test	The long non-coding RNA (LncRNA) (>200nt) proximate to each risk gene was explored in NCBI dbSNP and…
12	Materials and Methods — SNP-disease association test	and HumanOmni1_Quad_v1-0_B beadchips, respectively. The association analysis was performed using…
13	Results	The variants located within ADH cluster on Chr4 (32–35) were found to be significantly associated…
14	Results	within or between five loci were found to be suggestively (5×10−8<p<10−5) associated with…
15	Results	cis-eQTL analysis showed that rs2173201 between ADH1B and ADH1C, and rs4478858 at SERINC2 (10) had…
16	Results	When the expression of the aforementioned candidate genes was examined in the brains of mouse and…
17	Results	Bioinformatics analysis shows that 4 SNPs are located in the transcription factor binding sites…
18	Results	at SERINC2, rs750338 at PKNOX2, rs2842576 at NRD1, rs9825310 between GPD1L and CMTM8, and rs7916403…
19	Results	The LncRNA proximate to each risk gene is listed in Table 4. Twelve among the total 16 LncRNAs are…

Name	Type
acetyl-CoA	drug
ADH1A	gene
ADH1B	gene
ADH1C	gene
ADH4	gene
ADH5	gene
ADH6	gene
ADH antisense LncRNA local	gene
ADH cluster	gene
ADH genes	gene
ADH sense LincRNA local	gene
ADH variants local	variant
Affymetrix mouse whole genome oligonucleotide microarrays local	drug
African-Americans	cohort
African-American SAGE+COGA cohort local	cohort
African-American Yale cohort local	cohort
age	phenotype
Airway_epithelium local	anatomy
alcohol	phenotype
alcohol abuse	phenotype
alcohol dependence	phenotype
alcoholism	phenotype
alcohol sensitivity	phenotype
alcohol stimulated activity local	phenotype
ALDH2	gene
allele	cohort
Alzheimer's disease	phenotype
American adults	cohort
amplitude of the P300 response local	phenotype
ANKK1	gene
Asian	cohort
ASTN1 local	gene
attention deficit hyperactivity disorder	phenotype
Australian samples local	cohort
autism	phenotype
Autopsy frontal cortex cohort local	cohort
autosomal SNPs	cohort
Bidirectional LncRNA of HTR7 local	gene
bipolar disorder	phenotype
BN-Lx/ CubPrin local	cohort
brain	anatomy
Brugada syndrome 2 local	phenotype
BXD recombinant inbred panel local	cohort
C57BL/6J	cohort
central nervous system	anatomy
cerebellum	anatomy
CHRM2	gene
Chrna3	gene
CHRNA5	gene
Chrnb4	gene
chronic alcoholism	phenotype
Chronic_alcohol_use local	phenotype
cigarettes	phenotype
Circadian rhythms	phenotype
clozapine	drug
CMTM8	gene
CNV	variant
cocaine	phenotype
Cocaine_use_disorder local	phenotype
cognition	phenotype
comorbid alcoholism and depression	phenotype
COMT	gene
CoREST local	drug
CoREST	gene
cortex	anatomy
CRHR1	gene
Cufflinks	drug
DBA/2J	cohort
dementia	phenotype
depression	phenotype
diagnosis	phenotype
DRD2	gene
eating disorders	phenotype
EMX2OS local	gene
ethanol consumption	phenotype
European-American SAGE+COGA cohort local	cohort
European population	cohort
fatty acids	drug
folate deficiency	phenotype
frontal cortex	anatomy
FuncPred	drug
GABRA2	gene
Gabrg1	gene
gene variation local	variant
Germans	cohort
glucose	drug
GPD1L local	gene
GPD1L-CMTM8 variant local	variant
granule cells	anatomy
H19 local	gene
HapMap	cohort
HapMap CEU children population local	cohort
HapMap CEU parent population local	cohort
HapMap CEU parent sample local	cohort
HapMap YRI parent sample local	cohort
healthy donors local	cohort
heavy drinking	phenotype
Heroin abusers local	cohort
Heroin_use_disorder local	phenotype
high ethanol-consuming rats local	cohort
hippocampus	anatomy
HTR2B	gene
Htr7	gene
HTR7 risk SNP local	variant
human alcoholics	phenotype
human brain	anatomy
Illumina HiSeq2000 local	drug
KIAA0040	gene
Koreans	cohort
learning and memory	phenotype
limbic system	anatomy
liver	anatomy
lncRNA	drug
lncRNAs	drug
lymphoblastoid cell lines	cohort
MAOA	gene
Map3k9	gene
MAP3K9-PCNX variant local	variant
MEG3	gene
metal	drug
MFOLD local	drug
MIAT local	gene
mouse brain	anatomy
MREG	gene
MREG-PECR intergenic variant local	variant
NAc	anatomy
NCAM1	gene
NEAT1 local	gene
NEAT2 local	gene
Neural plasticity local	phenotype
neurons	phenotype
nicotine	drug
Non-replicable risk genes local	gene
NR_027085.1 local	gene
NR_034112.1 local	gene
NR_037195.1 local	gene
NR_037884.1 local	gene
NRD1 local	gene
nucleus accumbens	anatomy
obsessive-compulsive disorder	phenotype
OPA3 local	gene
OPA3 variant local	variant
Oprd1	cohort
OPRK1	cohort
OPRM1	cohort
PBMC healthy donor cohort local	cohort
PBMC samples local	cohort
PCNX local	gene
PECR	gene
Phosphatidylserine local	drug
PKNOX2	gene
PKNOX2 variant local	variant
Polyphen2	drug
PRC2	drug
PRC2 local	gene
psychiatric disorders	phenotype
Purkinje cells	anatomy
Red nucleus	anatomy
retinal local	drug
Retinal local	drug
retinoic acid	drug
risk genes	cohort
risk SNP at HTR7 local	variant
risk SNPs local	variant
Risk SNPs local	variant
risperidone	drug
RNA-seq	drug
rs1057239 local	variant
rs1229984	variant
rs1344694	variant
rs1789891	variant
rs1894709 local	variant
rs2066702	variant
rs2173201 local	variant
rs2275436 local	variant
rs2842576 local	variant
rs28864441	variant
rs36563 local	variant
rs4147541	variant
rs4478858 local	variant
rs4699748 local	variant
rs6425323 local	variant
rs6701037 local	variant
rs698	variant
rs750338	variant
rs7916403	variant
rs8111589 local	variant
rs9825310 local	variant
schizophrenia	phenotype
SCMX local	drug
SCMX local	gene
SERINC2	gene
serotonin	drug
sex	phenotype
SHR/OlaPrin local	cohort
SLC6A4	gene
sleep	phenotype
smoking	phenotype
SNP	cohort
SNP in HTR7 LncRNA local	variant
social phobia	phenotype
structural variant	cohort
substance use	phenotype
substantia nigra	anatomy
TCONS_00000180 local	gene
TCONS_00000690 local	gene
TCONS_00001448 local	gene
TCONS_00018282 local	gene
thalamocortical regions	anatomy
TNN local	gene
TNR local	gene
TopHat2 local	drug
triglycerides	phenotype
TTC12	gene
UCSC Genome Browser	drug
visual perception local	phenotype
Vitamin A	drug
whole brain	anatomy
XR_110219.3 local	gene

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JNK Signaling Positively Regulates Acute Ethanol Tolerance in <i>C. elegans</i>.	Jee C et al.	—	2024	→
Phenome-wide association studies between <i>SERINC2</i> and neuropsychiatric disorders.	Liu P et al.	—	2024	→
Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction.	Duttke SH et al.	—	2022	→
Identification of Novel Metabolic Subtypes Using Multi-Trait Limited Mixed Regression in the Chinese Population.	Ding K et al.	—	2022	→
Non-coding RNA in alcohol use disorder by affecting synaptic plasticity.	Zhu S et al.	—	2022	→
Heritability of ethanol consumption and pharmacokinetics in a genetically diverse panel of collaborative cross mouse strains and their inbred founders.	Bagley JR et al.	—	2021	→
SERINC2 increases the risk of bipolar disorder in the Chinese population.	Yang D et al.	—	2021	→
The Etiologic, Theory-Based, Ontogenetic Hierarchical Framework of Alcohol Use Disorder: A Translational Systematic Review of Reviews.	Boness CL et al.	—	2021	→
Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed 'Aging Cascade'.	Schreiter T et al.	—	2021	→
Genomic landscape of the signals of positive natural selection in populations of Northern Eurasia: A view from Northern Russia.	Khrunin AV et al.	—	2020	→
PIWI-interacting RNAs and PIWI proteins in glioma: molecular pathogenesis and role as biomarkers.	Tamtaji OR et al.	—	2020	→
Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence	McMichael GO et al.	—	2019	—
Cross-Species Co-analysis of Prefrontal Cortex Chronic Ethanol Transcriptome Responses in Mice and Monkeys.	Bogenpohl JW et al.	—	2019	→
ANCO-GeneDB: annotations and comprehensive analysis of candidate genes for alcohol, nicotine, cocaine and opioid dependence.	Hu R et al.	—	2018	→
Association of alcohol dehydrogenase 1C gene 1/2 polymorphism with alcohol Dependence(AD) in Turkey: A meta-analysis.	Zhang S et al.	—	2018	→
GABA<sub>A</sub> receptor polymorphisms in alcohol use disorder in the GWAS era.	Koulentaki M et al.	—	2018	→
Genetic contributions to precocity traits in racing Thoroughbreds.	Farries G et al.	—	2018	→
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	Prytkova I et al.	—	2018	→
Shared genetic etiology between alcohol dependence and major depressive disorder.	Foo JC et al.	—	2018	→
An association study revealed substantial effects of dominance, epistasis and substance dependence co-morbidity on alcohol dependence symptom count.	Chen G et al.	—	2017	→
A National Swedish Longitudinal Twin-Sibling Study of alcohol use disorders among males.	Long EC et al.	—	2017	→
Comorbidity of Alcohol Use Disorder and Chronic Pain: Genetic Influences on Brain Reward and Stress Systems.	Yeung EW et al.	—	2017	→
Emerging roles for ncRNAs in alcohol use disorders.	Mayfield RD	—	2017	→
A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction.	Bell RL et al.	—	2016	→
Genetics of Substance Use Disorders.	Yu C et al.	—	2016	→
piRNAs and Their Functions in the Brain.	Zuo L et al.	—	2016	→
Gene-based and pathway-based genome-wide association study of alcohol dependence.	Zuo L et al.	—	2015	→
The Pivotal Role of Aldehyde Toxicity in Autism Spectrum Disorder: The Therapeutic Potential of Micronutrient Supplementation.	Jurnak F	—	2015	→
The 5-HT7 receptor as a potential target for treating drug and alcohol abuse.	Hauser SR et al.	—	2014	→