Objective: We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs). Methods: A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis. Results: A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10-7≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4×10-7) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence. Conclusion: NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.

HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample (p < 0.05). The best novel signal was SNP rs2239803 associated with AD in both samples (p = 0.000817 for the COGA sample and p = 0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples (p = 0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples (p = 8.97 × 10-6 and 2.02 × 10-5 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples (p = 0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD.

OBJECTIVES: We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS: A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39 903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0

BACKGROUND: Alcohol dependence is more common among men than among women. Potential explanations for this include the role of genes in sex chromosomes (X and Y). In the present study, we scanned the entire Y chromosome and its homologs on the X chromosome in men to identify male-specific risk genes for alcohol dependence. METHODS: Two thousand nine hundred and twenty-seven individuals in two independent cohorts were analyzed. The European-American male cohort (883 cases with alcohol dependence and 445 controls) served as the discovery cohort and the European-American female cohort (526 cases and 1073 controls) served as a contrast group. All individuals were genotyped on the Illumina Human 1M beadchip. Two thousand two hundred and twenty-four single nucleotide polymorphisms (SNPs) on the Y chromosome or in the homologs on the X chromosome were analyzed. The allele frequencies were compared between cases and controls within each cohort using logistic regression analysis. RESULTS: We found that, after experiment-wide correction, two SNPs on the X chromosome were associated significantly with alcohol dependence in European-American men (P=1.0×10 for rs5916144 and P=5.5×10 for rs5961794 at 3′ UTR of NLGN4X), but not in the women. A total of 26 SNPs at 3′UTR of or within NLGN4X were nominally associated with alcohol dependence in men (5.5×10≤P≤0.05), all of which were not statistically significant in women. CONCLUSION: We conclude that NLGN4X was a significant male-specific risk gene for alcohol dependence in European-Americans. NLGN4X might harbor a causal variant(s) for alcohol dependence. A defect of synaptogenesis in neuronal circuitry caused by NLGN4X mutations is believed to play a role in alcohol dependence.

Variants (such as rs9939609) in the fat mass- and obesity-associated (FTO) gene have been associated with obesity, type 2 diabetes, some cancers, and alcohol consumption. This study tested the associations of 167 single-nucleotide polymorphisms (SNPs) within FTO gene with alcohol dependence (AD) using two Caucasian samples: the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis of AD as a binary trait was performed using the PLINK software. For the SAGE sample, the top three SNPs showing associations with AD were rs8062891, rs1108086, and rs1420318 (p = 0.00088, 0.00086 and 0.00086, respectively). Two SNPs (rs12597786 and rs7204609) associated with AD in the SAGE sample (p = 0.017 and 0.034, respectively) were replicated in the COGA sample (p = 0.017 and 0.014, respectively). Through meta-analysis of two samples using PLINK, the top three SNPs associated with AD were rs8062891, rs12597786, and rs7204609 (p = 0.00064, 0.00076 and 0.0011, respectively). Haplotype analysis in the SAGE sample further supported the associations with AD in single-marker analysis. In addition, we found association of rs17817449 (which has a strong linkage disequilibrium with rs9939609) with AD in the SAGE sample (p = 0.00339). The findings provide evidence of joint intervention and prevention of AD and obesity.

Objective: We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs). Methods: A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis. Results: A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10-7≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4×10-7) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence. Conclusion: NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.

HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample (p < 0.05). The best novel signal was SNP rs2239803 associated with AD in both samples (p = 0.000817 for the COGA sample and p = 0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples (p = 0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples (p = 8.97 × 10-6 and 2.02 × 10-5 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples (p = 0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD.

OBJECTIVES: We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS: A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39 903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0

Alcohol addiction may increase the risk of obesity due to shared genetic components. The Copine V (CPNE5) gene is involved in Ca2+ binding and may play an important role in the development of the central nervous system. This study tested the genetic associations of 77 single-nucleotide polymorphisms (SNPs) within the CPNE5 gene with alcohol dependence (AD) and obesity using a Caucasian sample - The Study of Addiction - Genetics and Environment (SAGE) sample (1066 AD cases and 1278 non-AD controls, 422 obese cases and 1395 non-obese controls). The Marshfield sample (1442 obese cases and 2122 non-obese controls) was used for replication of obesity. Multiple logistic regression analysis was performed using the PLINK software. In the SAGE sample, we identified 10 SNPs associated with AD and 17 SNPs associated with obesity (p < 0.05). Interestingly, 6 SNPs (rs9986517, rs9470387, rs3213534, rs10456444, rs3752482, and rs9470386) were associated with both AD (OR = 0.77, 0.77, 0.83, 0.84, 0.79 and 1.14, respectively; p = 9.72 × 10-5, 1.1 × 10-4, 4.09 × 10-3, 5.26 × 10-3, 1.59 × 10-2, and 3.81 × 10-2, respectively) and obesity (OR = 0.77, 0.77, 0.78, 0.77, 0.68 and 1.18, respectively; p = 2.74 × 10-3, 2.69 × 10-3, 2.45 × 10-3, 1.01 × 10-3, 5.18 × 10-3 and 3.85 × 10-2, respectively). In the Marshfield sample, rs3752480 was associated with obesity (p = 0.0379). In addition, four SNPs (rs9986517, rs10456444, rs7763347 and rs4714010) showed associations with obesity in the meta-analysis using both samples (p = 0.00493, 0.0274, 0.00346, and 0.0141, respectively). These findings provide the first evidence of common genetic variants in the CPNE5 gene influencing both the AD and obesity; and will serve as a resource for replication in other populations.

The DPYSL2 gene at 8p22-p21 is expressed widely in neuronal tissues and has been implicated in multiple psychiatric disorders such as Alzheimer's disease and schizophrenia. We therefore hypothesized that DPYSL2 gene polymorphisms may play a role in alcohol dependence (AD). We investigated the genetic associations of 57 single-nucleotide polymorphisms (SNPs) within the DPYSL2 gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls), and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). The SNP rs11995227 was most significantly associated with AD (p = 0.000122) in the COGA sample while one flanking SNP rs7832576 revealed the second most significant association with AD (p = 0.00163) in the COGA sample and association with AD (p = 0.0195) in the SAGE sample. Meta-analysis of two samples showed both rs119952227 and rs7832576 were associated with AD (p = 0.000363 and 0.000184, respectively). Furthermore, the C-A haplotype from rs11995227 and rs7832576 revealed significant association with AD (p = 0.0000899) in the COGA sample while the T-G haplotype revealed association with AD both in the COGA and SAGE samples (p = 0.00098 and 0.021, respectively). These findings suggest that genetic variants in DPYSL2 may play a role in susceptibility to AD.