Genetic Architecture and Risk Profile of Alcohol-Related Diseases

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Abstract
Alcohol consumption is a major public health challenge, linked to substantial morbidity and mortality worldwide. Despite known genetic influences on alcohol use, relatively little is known about the genetic determinants of specific alcohol-related disease endpoints. In this study, we leveraged the extensive FinnGen study, comprising over 500,000 individuals with up to 56 years of follow-up, to investigate the genetic architecture of 19 alcohol-attributable disease endpoints and 41 disease endpoints in which alcohol is a known risk factor. We identified 93 fine-mapped genetic loci associated with 13 alcohol-attributable disease endpoints, including 37 loci not previously linked to alcohol use or alcohol-attributable disease endpoints. Genetic correlations were strong between mental and behavioural disorders due to alcohol, while alcohol-attributable organ injuries exhibited more distinct genetic profiles. Using a polygenic risk score (PRS) for alcohol use, we demonstrated significant risk stratification for several alcohol-related diseases. For example, individuals in the highest PRS decile showed markedly elevated risks not only for numerous alcohol-attributable diseases (HR = 1.50; 95% CI: [1.46–1.55], compared to the 10th–90th PRS percentiles), but also for opioid use (HR = 1.59; 95% CI: [1.38–1.83]), and to a lesser extent, for several other endpoints. These findings elucidate the complex genetic landscape of alcohol-related diseases, highlighting the potential utility of genetic risk profiling in clinical settings to identify individuals at heightened risk for alcohol-related health complications.

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