Clinical, Environmental, and Genetic Factors Contribute to Risk for Substance Use Disorders

Abdullah Hashmi, MD, for Medscape

February 03, 2022

The study covered in this summary was published as a preprint and has not yet been peer-reviewed.

Key Takeaways

  • Clinical, environmental, and genetic risk measures show modest ability to distinguish between individuals for alcohol, drug, and any substance use disorders in young adulthood.

  • The predictive power of polygenic scores and a clinical/environmental/risk index (CERI) was tested by evaluating four longitudinal cohorts. It showed the association of CERI with DSM-IV criteria for alcohol dependence, drug dependence, and any substance dependence.

  • The polygenic scores for problematic alcohol use and externalizing were together associated with any substance dependence. The polygenic scores for problematic alcohol use by itself were associated with alcohol dependence, and the polygenic scores for externalizing by itself were associated with drug dependence.

Why This Matters

  • A major public health need exists to identify people at risk of substance use disorders given the substantial costs to affected individuals, their families, and society.

  • This data analysis provides initial evidence that each risk factor contributes unique information for substance use disorders in early adulthood.

  • Using these data and expanding sources of information will allow for improved precision in future screening tools to identify and intervene for those at greatest risk for developing substance use disorders.

Study Design

  • The joint association of early-life CERI and polygenic scores with substance use disorders was evaluated across four longitudinal cohorts. These cohorts (combined sample n = 15,134) included population samples from three countries (United States, England, Finland), with two samples including individuals of European and African ancestries.

  • Lifetime DSM-IV diagnosis of a substance use disorder included the nonmutually exclusive categories of alcohol dependence, drug dependence, and any substance dependence (alcohol, other drug, or nicotine) as the main outcome.

  • The CERI considered 10 early-life risk factors for substance use disorders, which were aggregated to measure risk. The polygenic scores were aggregates of the number of risk alleles carried by individuals weighted against recent genome-wide association studies of substance use disorders. Substance use disorders showed strong genetic overlap with other externalizing, internalizing, and psychotic disorders.

  • A series of nested logistic regression models with pooled data included a baseline model (sex, age, and cohort), a genetic risk model (baseline + polygenic scores), a clinical/environmental risk model (baseline + CERI), and a combined risk model (baseline + polygenic scores + CERI) to assess the predictive accuracy of each model. 

Key Results

  • The CERI model was associated with alcohol dependence, drug dependence, and any substance dependence (odds ratios [ORs], 1.35–1.64).

  • The overall predictive power of polygenic scores alone was in the range of 1.3% to 2.4%.

  • The polygenic scores for problematic alcohol use were associated with alcohol dependence (OR, 1.14), and polygenic scores for externalizing were associated with drug dependence (OR, 1.14).

  • The polygenic scores for problematic alcohol use and externalizing were associated with any substance dependence (ORs, 1.11–1.19).

  • The relative risk ratio was 3.82–9.13 for each substance use disorder in the top 10% of CERI and polygenic scores relative to the bottom 90%.


  • Although individuals of diverse ancestries were included, the polygenic scores for African-ancestry samples were based on a very small sample size. Large-scale, genome-wide association studies in diverse cohorts are needed.

  • The measure of environmental risk may not have fully captured risk factors and other social determinants that contribute to substance use disorders in populations beyond non-Hispanic White individuals.

  • Racially relevant measures of risk and other social and environmental measures that are known risk factors for substance use disorders were not well represented. 

  • Some risk factors (such as adolescent substance abuse) could have occurred concurrently with diagnosis. Samples that include risk factors measured before the substance use will be important for comparison.


  • The authors have declared no competing interests.

  • The study was supported by the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the Academy of Finland, the Scientific and Technological Research Council of Turkey, and the Sigrid Jusélius Foundation.

This is a summary of a preprint research study, "Predicting Substance Use Disorders: A Multifactorial Risk Index Combining Clinical, Environmental, and Genetic Risk Factors," written by Peter B. Barr of SUNY Downstate Health Sciences University, New York City, and colleagues on medRxiv, provided to you by Medscape. This study has not yet been peer reviewed. The full text of this study can be found on 

For more news, follow Medscape on Facebook, Twitter, Instagram, YouTube, and LinkedIn


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.