Greater Than the Sum of its Parts: Polygenic Risk Scores Identifiy People at Risk of Alcohol Use Disorder

Newswise — Scoring of common genetic variants can help identify people at high risk for alcohol use disorder (AUD), according to a study in Alcoholism: Clinical and Experimental Research. With prompt intervention, it may then be possible to prevent these individuals from developing AUD. For decades, a family history of AUD − which reflects both genetic and environmental risk − has been used to assess AUD liability. However, information on family history is not always available, and not all patients with AUD would be expected to have a positive family history. Therefore, relying on family history as the primary predictor of risk misses many high-risk individuals. For complex disorders like AUD, the common genetic variants that contribute to genetic risk each have a small effect on their own. However, when evaluated together, these variants can be used to calculate polygenic risk scores (PRS) – the weighted sum of multiple risk genes across the whole genome. PRS have shown promise in evaluating risk and identifying high-risk individuals in other conditions. Recently, large-scale genetic studies have revealed numerous genetic variants associated with AUD, making it possible to perform PRS analysis in AUD with sufficient statistical power. In the current study, researchers investigated whether PRS can be used to evaluate the risk for AUD and predict AUD severity, and compared the performance of PRS with measures of AUD family history.

The research team analyzed data from people of European ancestry who had provided samples for genetic analysis in another study, the Collaborative Study on the Genetics of Alcoholism (COGA). Within the study sample, over three thousand people met the diagnostic criteria for AUD or alcohol dependence (‘cases’), while over one thousand had consumed alcohol but did not have a history of AUD (‘controls’). Included individuals were also classified according to their AUD family history (i.e. having or not having a first-degree relative with AUD). The researchers calculated PRS for each individual, and performed statistical modeling to test for associations of PRS and family history with AUD, and with AUD severity as measured by the number of diagnostic criteria met by each individual.

They found that, on average, people with AUD (the ‘cases’) had a higher PRS than the controls, and that PRS increased with increasing AUD severity. Those with a PRS in the top 10% of the score range had twice the odds of having AUD as other participants. Family history was also effective in predicting AUD. Of note, however, PRS remained significantly associated with AUD and AUD severity even after adjusting for family history.

Overall, the findings indicate that while family history reflects at least part of the genetic risk for AUD, PRS provides complementary information, and together they improve the ability to evaluate risk. PRS may be especially useful when family history of AUD is not reported or unavailable. Like family history, PRS can be evaluated before the onset of AUD, allowing targeted interventions that enable individuals to make informed decisions about their alcohol use; for example, those at high risk may choose to abstain from drinking, preventing any possibility of developing AUD. Future studies are needed to extend the findings to non-European ancestries.

Evaluating risk for alcohol use disorder: Polygenic risk scores and family history.

D. Lai, E. C. Johnson, S. Colbert, G. Pandey, G. Chan, L. Bauer, M. W. Francis, V. Hesselbrock, C. Kamarajan, J. Kramer, W. Kuang, S. Kuo, S. Kuperman, Y. Liu, V. McCutcheon, Z. Pang, M. H.

Plawecki, M. Schuckit, J. Tischfield, L. Wetherill, Y. Zang, H. J. Edenberg, B. Porjesz, A. Agrawal, T. Foroud (pages xxx) ACER-21-5047.R1