Genetic Variants for Substance Use and Brain Structure Share Common Pathways | Research

The takeaway

A genetics study identified shared genetic links between brain cortical structure and substance use behaviors, finding that a common substance use genetic factor was associated with brain surface area differences in the ABCD study of adolescents.

Neurogeneticists; brain imaging researchers; scientists studying the biological basis of addiction.

Cannabis use genetics positively correlated with insula surface area

What the researchers found

Eight significant negative genetic correlations were found between brain measures and substance use, including between alcohol consumption and cortical thickness. Five positive correlations were found, including between insula surface area and lifetime cannabis use. Polygenic risk scores for substance use predicted brain structure variation in the ABCD adolescent cohort.

Why it matters

This study helps disentangle whether substance use changes brain structure or whether shared genetics underlie both. The finding that substance use genetic risk predicts brain differences in adolescents who have not yet used substances suggests genetics play a genuine role.

The numbers in context

71 brain imaging measures analyzed. 8 significant negative and 5 significant positive genetic correlations identified. Insula surface area positively correlated with cannabis use genetics. Substance use polygenic risk scores predicted brain structure in ABCD cohort.

How the study worked

Used GWAS summary statistics for 71 brain imaging measures and alcohol, tobacco, and cannabis use behaviors. Linkage disequilibrium score regression identified genetic correlations. Genomic structural equation modeling created a common substance use genetic factor. Polygenic risk scores were validated in the ABCD study.

What this study cannot tell us

GWAS are primarily conducted in European-ancestry populations. Genetic correlations indicate shared genetic architecture but do not prove causation. Brain measures were from adult samples while validation was in adolescents. Effect sizes of individual genetic variants are very small.

How to read the evidence

Moderate: large-scale genetic analysis with ABCD validation, though limited by European-ancestry focus and inability to prove causation.

When this study was published

Published in 2022.

The bigger picture

This complements studies showing brain differences in substance users by demonstrating that some of those differences may be genetically predetermined rather than caused by substance use itself. This has important implications for interpreting brain imaging studies in cannabis users.

Questions still open

Do the genetically-driven brain differences increase vulnerability to substance use, or do they reflect broader personality or cognitive traits? Would these genetic findings replicate in non-European populations?

Common questions

Does cannabis use change brain structure or are people with different brains more likely to use?

This study suggests both may be true. Genetic variants associated with substance use also predict brain structure differences, even in adolescents who have not used substances. This means some brain differences seen in cannabis users may be pre-existing rather than caused by use.

What brain area was linked to cannabis genetics?

The insula, a brain region involved in interoception (awareness of internal body states), craving, and decision-making, showed surface area variation associated with cannabis use genetics.

Read the original research

Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.

Cerebral cortex (New York, N.Y. : 1991), 32(4), 796-807

View on PubMed ↗Publisher’s paper ↗

Citation

Rabinowitz, Jill A; Campos, Adrian I; Ong, Jue-Sheng; García-Marín, Luis M; Alcauter, Sarael; Mitchell, Brittany L; Grasby, Katrina L; Cuéllar-Partida, Gabriel; Gillespie, Nathan A; Huhn, Andrew S; Martin, Nicholas G; Thompson, Paul M; Medland, Sarah E; Maher, Brion S; Rentería, Miguel E. (2022). Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.. Cerebral cortex (New York, N.Y. : 1991), 32(4), 796-807. https://doi.org/10.1093/cercor/bhab243