Family-based association analysis of alcohol dependence in the COGA sample and replication in the Australian twin-family study

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10(-3)), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 x 10(-6)) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 x 10(-5)) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 x 10(-5)). Furthermore, we found support for association of MAOA gene (P = 4.14 x 10(-4) for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 x 10(-9)), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 x 10(-7)) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.