A previous genome-wide linkage study of alcohol dependence (AD) in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The ASTN1 gene is in this region, a gene previously reported to be associated with substance abuse, bipolar disorder and schizophrenia. Using the same family data consisting of 330 individuals with phenotypic data and DNA, finer mapping of a 26 cM region centered on D1S196 was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair-wise linkage disequilibrium (LD) of r(2) < 0.8 using the HapMap CEU population. Significant FBAT P-values for SNPs within the ASTN1 gene were observed for four SNPs (rs465066, rs228008, rs6668092, and rs172917), the most significant, rs228008, within intron 8 had a P-value of 0.001. Using MQLS, which allows for inclusion of all families, we find three of these SNPs with MQLS P-values < 0.003. In addition, two additional neighboring SNPs (rs10798496 and rs6667588) showed significance at P = 0.002 and 0.03, respectively. Haplotype analysis was performed using the haplotype-based test function of FBAT for a block that included rs228008, rs6668092, and rs172917. This analysis found one block (GCG) over-transmitted and another (ATA) under-transmitted to affected offspring. Linkage analysis identified a region consistent with the association results. Family-based association analysis shows the ASTN1 gene significantly associated with alcohol dependence. The potential importance of the ASTN1 gene for AD risk may be related its role in glial-guided neuronal migration.
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