Abstract
Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability. There is growing evidence that PRS may prove useful for early identification of those at increased risk for certain diseases. The current potential of PRS for alcohol use disorders (AUD) remains an open question. Using data from both a population-based sample [the FinnTwin12 (FT12) study] and a high-risk sample [the Collaborative Study on the Genetics of Alcoholism (COGA)], we examined the association between PRSs derived from genome-wide association studies (GWASs) of (1) alcohol dependence/alcohol problems, (2) alcohol consumption, and (3) risky behaviors with AUD and other substance use disorder (SUD) criteria. These PRSs explain ~2.5–3.5% of the variance in AUD (across FT12 and COGA) when all PRSs are included in the same model. Calculations of area under the curve (AUC) show PRS provide only a slight improvement over a model with age, sex, and ancestral principal components as covariates. While individuals in the top 20, 10, and 5% of the PRS distribution had greater odds of having an AUD compared to the lower end of the continuum in both COGA and FT12, the point estimates at each threshold were statistically indistinguishable. Those in the top 5% reported greater levels of licit (alcohol and nicotine) and illicit (cannabis and opioid) SUD criteria. PRSs are associated with risk for SUD in independent samples. However, usefulness for identifying those at increased risk in their current form is modest, at best. Improvement in predictive ability will likely be dependent on increasing the size of well-phenotyped discovery samples.
Highlights
Alcohol misuse is one of the leading contributors to preventable mortality and morbidity worldwide[1,2,3]
We were interested in (1) which scores based on available genome-wide association studies (GWASs) provided the strongest association with alcohol use disorder, whether these scores explained unique variance in alcohol use disorders (AUD) in a conditional model, and how well these scores discriminated between cases and controls; (2) what the risk of AUD was for those at the upper end of the risk continuum compared to the bottom; and 3) the levels of substance use disorder criteria for individuals at the top 5% of the polygenic score continuum compared to remaining 95%
When we included all of the polygenic risk scores (PRS) in one model, all three PRS were associated with AUD criteria in Collaborative Study on the Genetics of Alcoholism (COGA)
Summary
Alcohol misuse is one of the leading contributors to preventable mortality and morbidity worldwide[1,2,3]. Identifying individuals at heightened risk for developing alcohol-related problems remains an important goal of medical practitioners. One important risk factor for alcohol misuse is one’s own genetic liability. Twin and Beyond being useful for research purposes, researchers have begun to examine the potential of PRS to predict risk for medical outcomes in clinical settings. PRS for coronary artery disease (CAD), atrial fibrillation (AF), type 2 diabetes (T2D), inflammatory bowel disease (IBS), and. Individuals in the top 5% of the PRS distributions had ~3 fold likelihood of having CAD, AF, T2D, IBS, or BC compared to the bottom 95%. Individuals in the top PRS decile were on average 13 kg heavier than those in the bottom decile[12] These studies demonstrate the potential for identifying individuals at heightened risk for various medical conditions using PRS. Given that AUD is a moderately heritable trait and GWAS for alcohol-related phenotypes are beginning to identify numerous variants associated with these outcomes, PRS for alcohol-related outcomes may be able to identify individuals at heightened risk of developing an AUD
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