Effects of genetic risk for alcohol dependence and onset of regular drinking on the progression to alcohol dependence: A polygenic risk score approach

Background: Prior studies have established the importance of genetic contributions to the etiology of alcohol dependence (AD), and suggested an early onset of alcohol use represents an initial marker of this genetic risk, which is associated with a more rapid progression to AD and increased risk for AD itself. Building on prior work, the current study examined whether the additive effects of AD risk variants predicted the rate of progression to AD from the onset of regular drinking, a drinking milestone with high clinical relevance to AD prevention. Methods: Data from 1501 European-ancestry adults from the University of California – San Francisco Family Alcoholism Study were used to examine whether polygenic risk scores for AD (PRS_AD) and age-at-onset of regular drinking contributed uniquely to the likelihood of having a lifetime AD diagnosis and the rate of progression from regular drinking to AD. Mixed effects logistic regression and Cox proportional hazards regression analyses were employed. Results: Increases in PRS_AD were associated with a faster progression from regular drinking to AD independent of age-at-onset of regular drinking. An independent effect of age-at-onset of regular drinking was also observed indicating that a one-year delay in regular drinking was associated with a 7% decrease in the hazard of progression to AD among drinkers with an early onset (≤ 18), but a 3% increase among drinkers with a late onset (> 18) of regular drinking. Conclusions: These results broaden our understanding of the contributions of measured genotypes underlying AD-risk on the etiology and clinical course of AD.