Copy number variations (CNVs) can alter the DNA sequence in blocks ranging from kilobases to megabases, involving more total nucleotides than single nucleotide polymorphisms. Yet, its impact in humans is far from fully understood. In this study, we investigate the relationship of genome-wide CNVs with brain function elicited by an alcohol cue in 300 participants with alcohol use disorders. First, we extracted refined neurobiological phenotypes, the brain responses to an alcohol cue versus a juice cue in the precuneus, thalamus and anterior cingulate cortex (ACC). Then, we correlated the CNVs with incidence frequency > 1% to the neurobiological phenotypes. One CNV region at 22q13.1 was identified to be associated with alcohol dependence severity and the brain response to alcohol cues. Specifically, the 22k base-pair homozygous deletion at 22q13.1 affects genes APOBEC3a and APOBEC3b. Carriers of this homozygous deletion show a significantly higher score in the alcohol dependence severity (P < 0.05) and increased response to alcohol cues in the precuneus (P < 10−12) than other participants. Tests of a mediation model indicate that the precuneus mediates the association between the homozygous deletions and alcohol dependence severity. Interestingly, the precuneus is not only anatomically and functionally connected to the ACC and thalamus (the main active regions to the alcohol cue), but also has the most predictive power to the alcohol dependence severity. These findings suggest that the homozygous deletion at 22q13.1 may have an important impact on the function of the precuneus with downstream implications for alcohol dependence.