Objective: To develop a highly polygenic risk score (PRS) for alcohol consumption and study whether it predicts alcohol-related morbidity and all-cause mortality. Design: Biobank-based prospective cohort study. Setting: FinnGen Study (Finland). Participants: 96,499 genotyped participants from the nationwide prospective FinnGen study and 36,499 participants from prospective cohorts (Health 2000, FINRISK, Twin Cohort) with detailed baseline data and up to 25 years of follow-up time. Main outcome measures: Incident alcohol-related morbidity and alcohol-related or all-cause mortality, based on hospitalizations, outpatient specialist care, drug purchases, and death reports. Results: In 96,499 FinnGen participants there were in total 4,785 first-observed incident alcohol-related health events. The PRS of alcohol consumption was associated with alcohol-related morbidity and the risk estimate (hazard ratio, HR) between the highest and lowest quintiles of the PRS was 1.67 [ 95 % confidence interval: 1.52-1.84], p=3.2*10-27). In 28,639 participants with comprehensive baseline data from prospective Health 2000 and FINRISK cohorts, 911 incident first alcohol-related events were observed. When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI=[1.26-1.99], p=8.2*10-5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI=[1.2-1.47], p=4.5e-08) in the adjusted model. In all 39,695 participants with self-reported alcohol consumption available, a 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (β=11.2 [9.85-12.58 g], p = 2.3*10-58). Conclusions: The PRS for alcohol consumption associates for both alcohol-related morbidity and all-cause mortality. These findings underline the importance of heritable factors in alcohol-related behavior and the related health burden. The results highlight how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.

Polygenic risk score of alcohol consumption predicts alcohol-related morbidity and all-cause mortality