Multiple genetic variants could predict who benefits from alcohol addiction drug microbiologystudy

Alcohol-related genetic variants influence the effects of a medication for treating alcohol use disorder (AUD), according to an innovative study. The findings point to opportunities for new research approaches and customized treatments for patients.

Medications are under-used in the treatment of AUD, prescribed to only 2% of patients diagnosed with the disorder in 2022. The drug topiramate, when used off-label to treat AUD, has been shown in trials to reduce heavy drinking days and alcohol-related problems.

Investigators at the University of Pennsylvania and Yale are exploring whether genetic variants associated with AUD influence the effectiveness of topiramate. Although previously, they found effects of a single genetic variant, subsequent studies did not support a moderating effect of the variant on treatment outcomes.

For the new study in Alcohol: Clinical and Experimental Research, they examined whether more comprehensive measures of genetic risk, called polygenic scores, could help predict the effects of topiramate. Polygenic scores have previously been used to help identify substance use disorders.

The researchers worked with data from 285 patients of European descent with AUD who were treated with either topiramate or placebo. All patients underwent genetic testing.

The researchers used existing large genetic databases of people of European ancestry to create polygenic scores that summed the effects of multiple genetic variants linked to four alcohol-related traits: problematic alcohol use (PAU), alcohol consumption (DPW), time to relapse after treatment (TR), and time to relapse to heavy drinking (THR).

Using statistical analysis, the authors explored the link between these measures of genetic risk and the effectiveness of topiramate in reducing heavy drinking days and alcohol-related problems.

They found that topiramate reduced both alcohol-related problems and heavy drinking days more than placebo. The effects of treatment on alcohol-related problems were significantly linked to three polygenic scores (PAU, TR, and THR). Patients with higher polygenic scores experienced greater effects of topiramate treatment on reducing alcohol-related problems than patients with lower genetic risk.

The study provides further evidence that genetic risk can moderate the effects of AUD medications and potentially help match patients to treatments most likely to benefit them. It also highlights polygenic scores as an alternative to single genetic variants for investigating interactions between genetics and medications in treating AUD.

Because treatment response is complex, influenced by many genetic variants of small effect, polygenic scores may be particularly useful in revealing moderating effects of genetic differences among patients.