A Systematic Single Nucleotide Polymorphism Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association With a Novel Susceptibility Gene ACN9

Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. With a sample of 262 densely affected families, a peak logarithm of odds (LOD) score for alcohol dependence of 2.9 was observed at D7S1799. The LOD score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14). To follow up on this linkage region, we systematically screened single nucleotide polymorphisms (SNPs) across a 2 LOD support interval surrounding the alcohol dependence peak.The SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. Across the 18-Mb region, genotyped by the Center for Inherited Disease Research (CIDR), 1340 SNPs were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families.Eight SNPs showed association with alcohol dependence at p.01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence.These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.