摘要
Background Alcohol dependence （AD） is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study （GWAS） is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology. Methods A genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples： 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans. Results Several genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene （ANKRDT） showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-likel （CYTL 1） genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531066 （P = 6.51×10^-8）. The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRDTor CYTL1 gene and alcohol consumption. Conclusion The evidence suggests that ANKRD7 and CYTL 1 genes may play an important role in the variance in AD risk.
Background Alcohol dependence （AD） is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study （GWAS） is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology. Methods A genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples： 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans. Results Several genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene （ANKRDT） showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-likel （CYTL 1） genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531066 （P = 6.51×10^-8）. The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRDTor CYTL1 gene and alcohol consumption. Conclusion The evidence suggests that ANKRD7 and CYTL 1 genes may play an important role in the variance in AD risk.
基金
This work was supported by grants from NIH （No. R21 AA015973, No. R21 AGO27110, No. R01 AR050496-01, No. R01 AG026564, and No. P50 AR055081）, National Science Foundation of China （No. 30771222 and No. 30731160618）, Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry of China （（2010） 609） and Innovative Program of Hunan Province （No. 2011TF1004）.
