<p>Alcohol use disorder (AUD) is a highly prevalent condition that is globally associated with increased morbidity and mortality. Transmission of AUD across generations is well known. Adverse health effects of alcohol misuse in persons with AUD are also well known. The effect of alcohol misuse in previous generations on gene expression in offspring potentially leading to increased disease burden are largely unknown. We conducted a study of familial use of alcohol contrasting individuals without parents or grandparents with AUD with individuals with either a parent with AUD or both a parent and grandparent with AUD. The study controlled for important sources of variation by including individuals with samples banked in early adolescence before substantial use of alcohol and other substances occurred. Mothers of the participants were queried about their prenatal use of alcohol and other substances. We found a large number of highly significant differences in gene expression between controls and those with an AUD parent or AUD parent and grandparent, allowing us to conclude that preconception use of high levels of alcohol is associated with differences in gene expression in offspring blood. Pathway enrichment analyses revealed a statistical over representation in those involving the immune system and cancer development.</p>