Family-based association studies of alcohol dependence and age at onset in the COGA sample

Background: Prior research has indicated that alcohol dependence and age at onset (AAO) of alcoholism are influenced by many genes. Family-based association studies are preferable to case-control studies in establishing allelic associations when working with a heterogeneous population. Also subgroup analysis has potential to reduce genetic heterogeneity.

Methods: We used 405 microsatellite markers genotyped in 211 Caucasian pedigrees (591 nuclear families) form the Collaborative Study on the Genetics of Alcoholism (COGA), as well as 4,720 SNPs from the Illumina panel and 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 122 Caucasian pedigrees (292 nuclear families) from GAW14 (a COGA sample subset). The phenotypes included alcohol dependence (ALDX1) as a binary trait and AAO as a quantitative trait. Family-based association analysis was performed by the FBAT program, and the contributions of maternal versus paternal gene transmission and gender of the affected subjects were all evaluated using the UNPHASED software.

Results: SNPs rs1367311 on chromosome 3 and rs742997 on the X-chromosome showed highly significant associations with alcohol dependence (p=7.3x10^-6 and p=5.98x10^-7, respectively). Several SNPs (rs1875355, rs1417578, rs726739, rs2884045, rs2394075 and rs751871) and one microsatellite marker (D12S391) demonstrated moderate associations (p<10^-4) with either alcohol dependence or AAO. Interestingly, SNP rs979606 in the MAOA gene showed associations with both alcohol dependence (p=1.09x10^-4) and AAO (p=8.8x10^-3), as did the marker D9S930 and SNP rs742997. In addition, several SNPs exhibited parent-of-origin effects and gender differences.

Conclusion: Our results have detected some genetic variants that are significantly associated with alcohol dependence and age at onset.