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A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.

ABSTRACT: Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies. The present study used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 European-American (EA) cases and 1,518 EA controls. The replicable associations were then subjected to secondary replication in a sample of 6,438 Australian family subjects. A functional expression quantitative trait locus (eQTL) analysis of these replicable risk SNPs was followed-up in order to explore their cis-acting regulatory effects on gene expression. We found that within a 90?Mb region around PHF3-PTP4A1 locus in AAs, a linkage disequilibrium (LD) block in PHF3-PTP4A1 formed the only peak associated with alcohol dependence at p<10(-4). Within this block, 30 SNPs associated with alcohol dependence in AAs (1.6×10(-5)?p?0.050) were replicated in EAs (1.3×10(-3)?p?0.038), and 18 of them were also replicated in Australians (1.8×10(-3)?p?0.048). Most of these risk SNPs had strong cis-acting regulatory effects on PHF3-PTP4A1 mRNA expression across three HapMap samples. The distributions of -log(p) values for association and functional signals throughout this LD block were highly consistent across AAs, EAs, Australians and three HapMap samples. We conclude that the PHF3-PTP4A1 region appears to harbor a causal locus for alcohol dependence, and proteins encoded by PHF3 and/or PTP4A1 might play a functional role in the disorder.

SUBMITTER: Zuo L

PROVIDER: S-EPMC3210123 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.

Zuo Lingjun L Zhang Clarence K CK Wang Fei F Li Chiang-Shan R CS Zhao Hongyu H Lu Lingeng L Zhang Xiang-Yang XY Lu Lin L Zhang Heping H Zhang Fengyu F Krystal John H JH Luo Xingguang X

PloS one 20111107 11

Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies. The present study used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 ...[more]

PMID: 22096494

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Project description: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.

Project description:Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset.The GWAS tested 524,396 single-nucleotide polymorphisms (SNPs). All SNPs with P < 10(-4) were subjected to the follow-up study. In addition, nominally significant SNPs from genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step.Five university hospitals in southern and central Germany.The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent.Significant association findings in the GWAS and follow-up study with the same alleles.The GWAS produced 121 SNPs with nominal P < 10(-4). These, together with 19 additional SNPs from homologues of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10(-9); rs1344694, P = 1.69 x 10(-8)). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence.This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.

Project description:Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant gene--KIAA0040--that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of -log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369 ? r ? 0.824; 2.8 × 10?? ? p ? 0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 × 10?¹¹ ? p ?1 .5 × 10??) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.

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A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.

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A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.

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