A Genomewide Association Study of Alcohol Dependence in the Irish Affected Sib Pair Study of Alcohol Dependence. A. E. Adkins1, L. M. Hack2, T. B. Bigdeli1, B. T. Webb2, J. C. Bettinger3, A. G. Davies3, M. S. Grotewiel4, C. A. Prescott5, D. M. Dick6, K. S. Kendler6, B. P. Riley6 1) Dept. of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA; 2) Dept. of Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA; 3) Dept. of Pharmacology and Toxicology, Dept. of Psychiatry, Virginia Commonwealth University, Richmond, VA; 4) Dept. of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA; 5) Dept. of Psychology, University of Southern California, Los Angeles, CA; 6) Dept. of Human and Molecular Genetics, Dept. of Psychiatry, Virginia Commonwealth University, Richmond, VA.

   Background: We report results from a genomewide association study (GWAS) in an ethnically homogeneous Irish sample (N=710 related cases,1755 population controls) with strong supporting evidence from VCU Alcohol Research Center (VCU ARC) model organism (MO) studies. Methods: GWAS cases from the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) were diagnosed using DSM-IV criteria. Affymetrix V6.0 arrays were genotyped at 3 separate core facilities and BeagleCall was used to call genotypes. IMPUTE2 and the 1000 Genomes reference haplotype panel (March 2012 freeze) were used to impute unmeasured genotypes. After QC filtering, imputation, and post-imputation filtering, 710 AD cases, 1755 controls and 8.2 million SNPs remained. Probabilities were converted to dosages with MACH2. Case/control association analysis was run using MQLS to correct for the non-independence of siblings. A sex weighted prevalence estimate of 8.9% was used for controls. We used a significance threshold of p<3.06E-8. FDR q-values were calculated with QVALUE in R. Results: Site effects were well corrected by BeagleCall and p-values showed little inflation (=1.05). SNPs in the collagen 6A3 (COL6A3, N=12) gene on chromosome 2 and an intergenic region of chromosome 3 (N=1) were genomewide significant. 725 SNPs in 103 independent loci had q-values 0.5. Preliminary experimental data using multiple MOs support 3 of the top 5 genes: COL6A3 (top SNP p=6.18E-9,q=0.07), the Krueppel-like factor 12 (KFL12) gene on chromosome 13 (top SNP p=1.16E-7,q=0.08), and the Ryanodine receptor 3 (RYR3) gene on chromosome 15 (top SNP p=1.69E-7,q=0.08). Inactivation of one of three genes in C. elegans showing homology to human COL6A3 results in an ethanol resistance phenotype. The C. elegans klf-3 mutant (orthologous to human KLF12) does not develop acute functional tolerance to ethanol and RNAi knockdown of the D. melanogaster homolog of KLF12, luna, results in enhanced sensitivity to ethanol. Finally, a loss of function allele of unc-68, the C. elegans homolog of RYR3, confers resistance to ethanol. Discussion: Our case-control GWAS of AD detected significant association signal in COL6A3 based on 12 non-independent SNPs. Emerging evidence from the VCU ARC MO investigations provides strong additional support for 3 of the top 5 genes in our p-value ranked SNP list. Replication is underway for our top 725 SNPs in 4 independent samples of European descent (N>11,000).

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